Anti-allergy benzocycloheptathiophene derivatives

ABSTRACT

The present invention provides inhibitors of allergy, and allergic reactions specifically compounds of the present invention are described by the following chemical Formula I: 
                         
A method for treating an allergic reaction, or allergy diseases or disorders includes administering a therapeutically effective composition comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof and a pharmaceutically acceptable carrier, vehicle or excipient to a subject in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Phase Patent Application and claimspriority to and benefit of International Application NumberPCT/CN2012/077591, filed on Jun. 27, 2012, which claims priority to andbenefit of U.S. Provisional Application No. 61/502,066, filed on Jun.28, 2011, the entire disclosures of which are incorporated herein byreference.

BACKGROUND

The statements in this section merely provide background informationrelated to the present disclosure and may not constitute prior art.

Allergy is a complex disease. Multiple immune cells and inflammatorymediators contribute to the initiation and manifestation of allergicdiseases. In addition to the blockade of histamine H1 receptor, theanti-inflammatory effects have increasingly been recognized to play animportant role in the management of allergic diseases. Theanti-inflammatory effects include stabilization of mast cells (toprevent mediator release), blockade of lipid mediators such asplatelet-activating factor (PAF) and leukotrienes, inhibition ofadhesion molecules, and inhibition of eosinophils and CD4 T cells.

Allergic diseases have reached epidemic proportions worldwide. Allergicdiseases such as asthma, rhinitis or atopic dermatitis affect at least8%-16% population with the annual economic burden of 12.7, 1.2, and 3.8billion dollars, respectively, in the United States and are a majorhealth burden world-wide. The range of allergic diseases includesrhinitis, sinusitis, conjunctivitis, asthma, dermatitis and foodallergy. These diseases negatively impact the patient's quality of lifeand impair their ability to perform in school or workplace. Thus,allergic diseases result in significant socio-economic costs.

Mast cells play a major role in allergy through secretion of granuleassociated and newly synthesized mediators. They are distributed widelyin the body and are especially abundant in skin or mucosa where they caninteract with foreign materials such as allergens or pathogens. Mastcells possess a large number of high affinity IgE receptors on theirsurface. Allergen binding to IgE receptors on mast cells initiates acascade of signaling events leading to the production of potentinflammatory mediators including histamine, platelet-activating factor,IL-6 and many others.

The role of histamine in the pathophysiology of allergic disorders hasbeen well-recognized. Mast cells produce and store histamine in theirgranules. Upon allergen activation, mast cells immediately (withinseconds) release histamine into local tissues. Histamine exerts itseffects in allergic diseases primarily through interacting withhistamine H1 receptors which are present in a variety of organs such asnerve endings, blood vessel walls, and airway smooth muscles. Histaminehas broad biological effects. Depending on the location where histamineis released, its biological effects vary from mild discomfort of itch tolife-threatening bronchoconstriction. In the nose or skin, histamineinduces vasodilation and increases vascular permeability leading toedema and erythema. It stimulates the sensory nerve endings leading toitching or sneezing. In the lung, histamine provokes the bronchialsmooth muscle leading to bronchoconstriction.

H1 antihistamine agents play a pivotal role in the treatment of allergicdiseases and are among the most prescribed medications in the world.Depending on their action on the central nervous system, H1antihistamines are classified as first-generation and second-generation.In general, first-generation H1 antihistamines such asdexchlorpheniramine, hydroxyzine, contain two features that limit theirusage. One, they are rapidly absorbed and metabolized. Thus, they needto be administered 3 to 4 times a day. Second, they are highlylipophilic and easily cross the blood-brain barrier causing a major sideeffect of sedation. Thus, major efforts have been made to improve H1antihistamine agents by reducing their side effects on central nervoussystem and by enhancing the duration of drug effect.

Accordingly, there is a need for newer anti-allergy agents aimed atimproved efficacy and reduced side effects.

SUMMARY

The following only summarizes certain aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below. All references cited inthis specification are hereby incorporated by reference in theirentirety. In the event of a discrepancy between the express disclosureof this specification and the references incorporated by reference, theexpress disclosure of this specification shall control.

The invention comprises compounds of Formula I that inhibit histamineand allergic reactions and pharmaceutical compositions thereof. Theinvention is also directed to methods of inhibiting allergichypersensitivity and for treating allergy, or allergic conditions ordiseases in a subject in need thereof.

A first aspect of the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt, solvate or prodrug thereof,wherein

R₂ is each independently C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy,alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀aralkyl, aralkyloxy, C₄₋₁₀ heteroaryl, or C₄₋₁₀ heteroaralkyl, whereineach C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl,aralkyloxy, C₄₋₁₀ heteroaryl, or C₄₋₁₀ heteroaralkyl optionallyincluding 1-3 substituents independently selected from Q₁ or Q₂;

R₃ is each independently, hydrogen, halo, OH, —CN, —NO₂, —N═O, —NHOQ₁,—OQ₁, —SOQ₁, —SO₂Q₁, —SON(Q₁)₂, —SO₂N(Q₁)₂, —N(Q₁)₂, —C(O)OQ₁, —C(O)Q₁,—C(O)N(Q₁)₂, —C(═NQ₁)NQ₁-, —NQ₁C(═NQ₁)NQ₁-, —C(O)N(Q₁)(OQ₁),—N(Q₁)C(O)-Q₁, —N(Q₁)C(O)N(Q₁)₂, —N(Q₁)C(O)O-Q₁, —N(Q₁)SO₂Q₁,—N(Q₁)SOQ₁, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy,C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl,aralkyloxy, C₄₋₁₀ heteroaryl, or C₄₋₁₀ heteroaralkyl, wherein each C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl,C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, or C₄₋₁₀ heteroaralkyl optionally substituted with 1-3substituents independently selected from Q₁ or Q₂;

each Q₁ is independently hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, alkoxy,alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ arylalkyl, aralkyloxy,C₄₋₁₀ heterocyclic, or C₄₋₁₀ heteroaryl ring, each optionally including1-3 substituents independently selected from Q₂;

each Q₂ is halo, haloalkyl, oxo, oxime, azido, amino, amido, cyano, ON,NO₂, CF₃, OCF₃, OH, —COOH or C₁-C₄ alkyl optionally substituted with 1-3of halo, oxo, oxime, —ON, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)₃H, —NH₂, or—COOH.

The R₂ Variable

In some embodiments, R₂ is each independently C₁₋₈ alkyl, C₁₋₈ alkenyl,C₁₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, or C₄₋₁₀ heteroaralkyl, wherein each C₁₋₈ alkyl, C₁₋₈alkenyl, C₁₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, or C₄₋₁₀ heteroaralkyl optionally substituted with 1-3substituents independently selected from hydrogen, C₁₋₈ alkyl, C₁₋₈alkenyl, alkoxy, alkenoxy, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, aralkyloxy, or heteroaryl, wherein each C₁₋₈ alkyl, C₁₋₈alkenyl, alkoxy, alkenoxy, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, aralkyloxy, or heteroaryl optionally including 1-3substituents independently selected from halo, oxo, oxime, azido, amino,amido, cyano, ON, NO₂, CF₃, OCF₃, OH, —COOH or C₁-C₄ alkyl optionallysubstituted with 1-3 of halo, oxo, oxime, —ON, —NO₂, —CF₃, —OCF₃, —OH,—SH, —S(O)₃H, —NH₂, or —COOH. In another aspect, R₂ is C₁₋₈ alkyl, C₁₋₈alkenyl, C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, or C₄₋₁₀heteroaryl. In another aspect, R₂ is C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl or C₄₋₁₀ heteroaryl. In some aspects, R₂ is a C₄₋₁₀heterocycloalkyl or C₄₋₁₀ heteroaryl.

In some aspects, R₂ is piperidine, pyridine, azabenzimidazole,benzoimidazolyl, benzofuryl, benzofurazanyl, benzopyrazolyl,benzothiazolyl, benzothienyl, benzotriazolyl, benzothiophenyl,benzoxazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, furanyl,imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuryl,isochromanyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl,tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl,piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuryl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuryl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydropyrimidinyl,dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl,dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl,dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuryl,tetrahydrothienyl, tetrahydroquinolinyl, 2,3-dihydrobenzofuryl,2,3-dihydrobenzo-1,4-dioxinyl, imidazo(2,1-b)(1,3)thiazole, andbenzo-1,3-dioxolyl. pyridine-N-oxide, 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, N-methyl-piperidinyl, N-ethyl-piperidinyl,N-propyl-piperidinyl, hexahydrothiopyranyl, azepanyl, methylazepanyl,tetrahydropyranyl, piperidinylmethyl, pyridinyl, pyridinylmethyl,tetrahydrothiopyranyl, dioxolanylmethyl, dioxanylmethyl.N-isopropyl-piperidinyl, N-butyl-piperidinyl, N-pentyl-piperidinyl,N-hexylpiperidinyl, N-cyclohexyl-piperidinyl, N-acetyl-piperidinyl, orN-benzyl-piperidinyl. In some aspects, R₂ is pyridine.

The R₃ Variable

In some embodiments, R₃ is each independently hydrogen, halo, OH, —CN,—NO₂, —N═O, —NHOQ₁, —OQ₁, —SOQ₁, —SO₂Q₁, —SON(Q₁)₂, —SO₂N(Q₁)₂, —N(Q₁)₂,—C(O)OQ₁, —C(O)Q₁, —C(O)N(Q₁)₂, —C(═NQ₁)NQ₁-, —NQ₁C(═NQ₁)NQ₁-,—C(O)N(Q₁)(OQ₁), —N(Q₁)C(O)-Q₁, —N(Q₁)C(O)N(Q₁)₂, —N(Q₁)C(O)O-Q₁,—N(Q₁)SO₂Q₁, —N(Q₁)SOQ₁, C₁₋₈ alkyl, C₂₋₈ alkenyl, alkoxy, alkenoxy,C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl,aralkyloxy, C₄₋₁₀ heteroaryl, C₄₋₁₀ heteroaralkyl, wherein each C₁₋₈alkyl, C₂₋₈ alkenyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, C₄₋₁₀ heteroaralkyl optionally substituted with 1-3substituents independently selected from halo, haloalkyl, oxo, oxime,azido, amino, amido, cyano, CN, NO₂, CF₃, OCF₃, OH, —COOH or C₁-C₄ alkyloptionally substituted with 1-3 of halo, oxo, oxime, —CN, —NO₂, —CF₃,—OCF₃, —OH, —SH, —S(O)₃H, —NH₂, or —COOH.

each Q₁ is independently hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, alkoxy,alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ arylalkyl, aralkyloxy,C₄₋₁₀ heterocyclic, or C₄₋₁₀ heteroaryl ring, each optionally including1-3 substituents independently selected from Q₂;

each Q₂ is halo, haloalkyl, oxo, oxime, azido, amino, amido, cyano, CN,NO₂, CF₃, OCF₃, OH, —COOH or C₁-C₄ alkyl optionally substituted with 1-3of halo, oxo, oxime, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)₃H, —NH₂, or—COOH. In some aspects, R₃ is each independently selected from H, C₁₋₈alkyl, C₁₋₈ alkenyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, C₄₋₁₀ heteroaralkyl. In another aspect, R₃ is H or C₁₋₈alkyl. In another aspect, R₃ is hydrogen, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, hexyl, 2-ethylpropyl, and cyclohexyl. Insome aspects, R₃ is hydrogen or methyl.

In a second aspect, the invention is directed to a pharmaceuticalcomposition which comprises a compound of Formula I or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier, excipient, or diluent.

In a third aspect, the invention comprises a method of inhibiting anallergic response, for example, an anti-histamine response,stabilization of mast cells (to prevent mediator release), blockade oflipid mediators such as platelet-activating factor (PAF) andleukotrienes, inhibition of adhesion molecules and inhibition ofeosinophils and inhibition of CD4 T-cell cytotoxicity, the methodcomprising contacting a cell with a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, or with apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula I and a pharmaceutically acceptable carrier,excipient, or diluent.

In a fourth aspect, the invention provides a method for treating anallergic disease, disorder, or syndrome, the method comprisingadministering to a subject a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula I and a pharmaceutically acceptable carrier, excipient, ordiluent.

In a further aspect, the present invention provides an ophthalmiccomposition comprising a compound of formula I and an ophthalmicacceptable excipient, carrier or vehicle.

Further areas of applicability will become apparent from the descriptionprovided herein. It should be understood that the description andspecific examples are intended for purposes of illustration only and arenot intended to limit the scope of the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings described herein are for illustration purposes only and arenot intended to limit the scope of the present disclosure in any way.

FIG. 1A depicts the treatment schedule for allergy testing in vivo usingdinitrofluorobenzene (DNFB) and inhibition of allergic responses withketotifen and Compound A in mice.

FIG. 1B depicts graphical representation of the anti-allergy effects ofCompound A on ear and foot swelling in vivo experiments.

FIG. 2A depicts the treatment schedule for anti-histamine and mast cellstabilization testing in vivo using dinitrophenyl (DNP) using the Evan'sblue leakage protocol and inhibition of allergic responses withketotifen and Compound A in mice.

FIG. 2B depicts graphical representation of the inhibitory effects ofCompound A against mast cell mediator-induced vascular permeability invivo.

FIG. 3A depicts a dosing schedule for testing the anti-allergy effectsof Compound A in an in vivo DNFB challenge model measuring IgE-mediatedlate phase cutaneous reactions.

FIG. 3B depicts graphic representation of the anti-allergic effects ofCompound A in an in vivo mouse IgE-mediated late phase cutaneouschallenge using DNFB in pre-sensitized mice.

FIG. 4 depicts cytokine (IL-6) expressing inhibitory activity ofCompound A in sensitized mouse bone marrow derived mast cells stimulatedwith trinitrophenol-bovine serum albumin (TNP-BSA).

FIG. 5 depicts a bar graph illustrating inhibition of eosinophilproliferation in vitro by4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one(Compound A) and ketotifen. Asterix denotes statistical significancebetween the two groups.

DETAILED DESCRIPTION

The following description is merely exemplary in nature and is notintended to limit the present disclosure, application, or uses.

The following description of technology is merely exemplary in nature ofthe subject matter, manufacture and use of one or more inventions, andis not intended to limit the scope, application, or uses of any specificinvention claimed in this application or in such other applications asmay be filed claiming priority to this application, or patents issuingtherefrom. The following definitions and non-limiting guidelines must beconsidered in reviewing the description of the technology set forthherein.

The headings (such as “Introduction” and “Summary”) and sub-headingsused herein are intended only for general organization of topics withinthe present technology, and are not intended to limit the disclosure ofthe present technology or any aspect thereof. In particular, subjectmatter disclosed in the “Introduction” may include novel technology andmay not constitute a recitation of present technology. Subject matterdisclosed in the “Summary” is not an exhaustive or complete disclosureof the entire scope of the technology or any embodiments thereof.Classification or discussion of a material within a section of thisspecification as having a particular utility is made for convenience,and no inference should be drawn that the material must necessarily orsolely function in accordance with its classification herein when it isused in any given composition.

The citation of references herein does not constitute an admission thatthose references are present technology or have any relevance to thepatentability of the technology disclosed herein. Any discussion of thecontent of references cited in the Introduction is intended merely toprovide a general summary of assertions made by the authors of thereferences, and does not constitute an admission as to the accuracy ofthe content of such references. All references cited in the“Description” section of this specification are hereby incorporated byreference in their entirety.

The description and specific examples, while indicating embodiments ofthe technology, are intended for purposes of illustration only and arenot intended to limit the scope of the technology. Moreover, recitationof multiple embodiments having stated features is not intended toexclude other embodiments having additional features, or otherembodiments incorporating different combinations of the stated features.Specific examples are provided for illustrative purposes of how to makeand use the compositions and methods of this technology and, unlessexplicitly stated otherwise, are not intended to be a representationthat given embodiments of this technology have, or have not, been madeor tested.

As used herein, the words “preferred” and “preferably” refer toembodiments of the technology that afford certain benefits, undercertain circumstances. However, other embodiments may also be preferred,under the same or other circumstances. Furthermore, the recitation ofone or more preferred embodiments does not imply that other embodimentsare not useful, and is not intended to exclude other embodiments fromthe scope of the technology.

As referred to herein, all compositional percentages are by weight ofthe total composition, unless otherwise specified. As used herein, theword “include,” and its variants, is intended to be non-limiting, suchthat recitation of items in a list is not to the exclusion of other likeitems that may also be useful in the materials, compositions, devices,and methods of this technology. Similarly, the terms “can” and “may” andtheir variants are intended to be non-limiting, such that recitationthat an embodiment can or may comprise certain elements or features doesnot exclude other embodiments of the present technology that do notcontain those elements or features.

Disclosure of values and ranges of values for specific parameters (suchas temperatures, molecular weights, weight percentages, etc.) are notexclusive of other values and ranges of values useful herein. It isenvisioned that two or more specific exemplified values for a givenparameter may define endpoints for a range of values that may be claimedfor the parameter. For example, if Parameter X is exemplified herein tohave value A and also exemplified to have value Z, it is envisioned thatparameter X may have a range of values from about A to about Z.Similarly, it is envisioned that disclosure of two or more ranges ofvalues for a parameter (whether such ranges are nested, overlapping ordistinct) subsume all possible combination of ranges for the value thatmight be claimed using endpoints of the disclosed ranges. For example,if parameter X is exemplified herein to have values in the range of1-10, or 2-9, or 3-8, it is also envisioned that Parameter X may haveother ranges of values including 1-9, 1.1-9.9, 1-8, 1-3, 1-2, 2-10, 2-8,2-3, 3-10, and 3-9.

Although the open-ended term “comprising,” as a synonym of terms such asincluding, containing, or having, is used herein to describe and claimthe present invention, the invention, or embodiments thereof, mayalternatively be described using more limiting terms such as “consistingof” or “consisting essentially of” the recited ingredients.

ABBREVIATIONS AND DEFINITIONS

The following abbreviations and terms have the indicated meaningsthroughout:

Abbreviation Meaning br broad ° C. degrees Celsius CBZ CarboBenZoxy =benzyloxycarbonyl d doublet dd doublet of doublet dt doublet of tripletEI Electron Impact ionization Et Ethyl g gram(s) GC gas chromatography hor hr hour(s) HPLC high pressure liquid chromatography L liter(s) Mmolar or molarity m Multiplet Me Methyl mg milligram(s) MHz megahertz(frequency) Min minute(s) mL milliliter(s) mM Millimolar mmolmillimole(s) mol mole(s) MS mass spectral analysis N normal or normalitynM Nanomolar NMR nuclear magnetic resonance spectroscopy p.o. per Oral qQuartet RT Room temperature s Singlet s- Secondary t- Tertiary t or trTriplet TFA trifluoroacetic acid THF Tetrahydrofuran μL microliter(s) μMMicromole(s) or micromolar

The symbol “—” means a single bond, “═” means a double bond, “≡” means atriple bond, and “

” means a single bond and optionally a double bond. When chemicalstructures are depicted or described, unless explicitly statedotherwise, all carbons are assumed to have hydrogen substitution toconform to a valence of four.

“Administration” and variants thereof (e.g., “administering” a compound)in reference to a compound of the invention means introducing thecompound or a prodrug of the compound into the system of the animal inneed of treatment. When a compound of the invention or prodrug thereofis provided in combination with one or more other active agents (e.g.,anti-histamine, anti-inflammatory, antibiotic, etc.), “administration”and its variants are each understood to include concurrent andsequential introduction of the compound or prodrug thereof and otheragents.

If a group “R” is depicted as “floating” on a ring system, as forexample in the Formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused or bridged ringsystem, as for example in the Formula e:

then, unless otherwise defined, a substituent “R” may reside on any atomof the fused or bridged ring system, assuming replacement of a depictedhydrogen (for example the —NH— in the Formula above), implied hydrogen(for example as in the Formula above, where the hydrogens are not shownbut understood to be present), or expressly defined hydrogen (forexample where in the Formula above, “Z” equals ═CH—) from one of thering atoms, so long as a stable structure is formed. In the exampledepicted, the “R” group may reside on either the 5-membered or the6-membered ring of the fused or bridged ring system.

When a group “R” is depicted as existing on a ring system containingsaturated carbons, as for example in the Formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. In another example, twoR's on the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring structure with the depicted ring as forexample in the Formula:

“Alkenyl” or “lower alkenyl” means a straight or branched hydrocarbonradical having from 2 to 8 carbon atoms and at least one double bond andincludes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyland the like.

“Alkenylcarbonyl” means a C(O)R group where R is alkenyl, as definedherein.

“Alkenyloxy” or “lower alkenyloxy” means an —OR group where R isalkenyl, as defined herein. Representative examples include methoxy,ethoxy, 1-methoxyprop-1-en-3-yl, propoxy, isopropoxy, cyclopropyloxy,cyclohexyloxy and the like.

“Alkoxy” or “lower alkoxy” means an —OR group where R is alkyl, asdefined herein. Representative examples include methoxy, ethoxy,1-methoxyprop-1-en-3-yl, propoxy, isopropoxy, cyclopropyloxy,cyclohexyloxy and the like.

“Alkoxyalkyl” means an alkyl group, as defined herein, substituted withone, two, or three alkoxy groups, as defined herein.

“Akoxycarbonyl” means a —C(O)OR group where R is alkyl as definedherein.

“Alkoxycarbonylalkyl” means an alkyl group, as defined herein,substituted with one, two, or three alkoxycarbonyl groups, as definedherein.

“Alkyl” or “lower alkyl” means a linear or branched hydrocarbon grouphaving one to eight carbon atoms. Examples of lower alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl,pentyl, hexyl, heptyl, octyl and the like. A “C₀” alkyl (as in“C₀-C₆-alkyl”) is a covalent bond. “C₆ alkyl” refers to, for example,n-hexyl, iso-hexyl, and the like.

“Alkylamino” means a —NHR radical where R is alkyl as defined herein, oran N-oxide derivative thereof, e.g., methylamino, ethylamino, n-,iso-propylamino, n-, iso-, tert-butylamino, or methylamino-N-oxide, andthe like.

“Alkylaminoalkyl” means an alkyl group substituted with one or twoalkylamino groups, as defined herein.

“Alkylaminoalkyloxy” means an —OR group where R is alkylaminoalkyl, asdefined herein.

“Alkylcarbonyl” means a C(O)R group where R is alkyl, as defined herein.

“Alkylcarbonylamino” means a —NRC(O)R′ group where R is hydrogen oralkyl, as defined herein, and R′ is alkyl, as defined herein.

“Alkylene” refers to straight or branched divalent hydrocarbon,containing no unsaturation and having from two to eight carbon atoms.Examples of alkylene include eth-diyl (—CH₂CH₂—), prop-1,3-diyl(—CH₂CH₂CH₂—), 2,2-dimethylprop-1,3-diyl (—CH₂C(CH₃)₂CH₂—), and thelike.

“Alkylsulfonyl” means a —S(O)₂R group where R is alkyl, as definedherein.

“Alkylthio” means a —SR group where R is alkyl, as defined herein.Examples of alkylthio include methylthio and ethylthio, and the like.

“Alkylthioalkyl” means an alkyl group substituted with one or twoalkylthio groups, as defined herein, e.g. 2-(methylthio)-ethyl and2-(ethylthio)-ethyl.

“Alkynyl” or “lower alkynyl” means a straight or branched hydrocarbonradical having from 2 to 6 carbon atoms and at least one triple bond andincludes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.

“Amino” means a —NH₂.

“Aminoalkyl” means an alkyl group substituted with at least one,specifically one, two, or three, amino groups.

“Aminoalkyloxy” means an —OR group where R is aminoalkyl, as definedherein.

“Aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Representativeexamples include phenyl, naphthyl, and indanyl, and the like.

“Arylalkyl” means an alkyl group, as defined herein, substituted withone or two aryl groups, as defined herein. Examples include benzyl,phenethyl, phenylvinyl, phenylallyl and the like.

“Aryloxy” means a —OR group where R is aryl as defined herein.

“Arylalkyloxy” means a —OR group where R is arylalkyl as defined herein.

“Arylsulfonyl” means a —SO₂R group where R is aryl as defined herein.

“Carboxyalkyl” means an alkyl group, as defined herein, substituted withone, two, or three —C(O)OH groups.

“Carboxy ester” means a —C(O)OR group where R is lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, aryl or arylalkyl, each of which isdefined herein. Representative examples include methoxycarbonyl,ethoxycarbonyl, and benzyloxycarbonyl, and the like.

“Cyanoalkyl” means an alkyl, alkenyl, or alkynyl radical, as definedherein, substituted with at least one, specifically one, two, or three,cyano groups.

“Cycloalkyl” means a monocyclic or polycyclic hydrocarbon radical havingthree to thirteen carbon atoms. The cycloalkyl can be saturated orpartially unsaturated, but cannot contain an aromatic ring. Cycloalkylincludes fused, bridged, and spiro ring systems. Examples of suchradicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

“Cycloalkylalkyl” means alkyl group substituted with one or twocycloalkyl group(s), as defined herein. Representative examples includecyclopropylmethyl and 2-cyclobutyl-ethyl, and the like.

“Cycloalkylcarbonyl” means a —C(O)R group where R is cycloalkyl asdefined herein.

“Dialkylamino” means a —NRR′ radical where R and R′ are independentlyalkyl as defined herein, or an N-oxide derivative, or a protectedderivative thereof, e.g., dimethylamino, diethylamino,N,N-methylpropylamino or N,N-methylethylamino, and the like.

“Dialkylaminoalkyl” means an alkyl group substituted with one ordialkylamino group(s), as defined herein.

“Dialkylaminoalkyloxy” means an —OR group where R is dialkylaminoalkyl,as defined herein.

“Fused ring system” and “fused ring” refer to a polycyclic ring systemthat contains bridged or fused rings; that is, where two rings have morethan one shared atom in their ring structures. In this application,fused-polycyclics and fused ring systems are not necessarily allaromatic ring systems. Typically, but not necessarily, fused-polycyclicsshare a vicinal set of atoms, for example naphthalene or1,2,3,4-tetrahydro-naphthalene. A spiro ring system is not afused-polycyclic by this definition, but fused polycyclic ring systemsof the invention may themselves have spiro rings attached thereto via asingle ring atom of the fused-polycyclic. In some examples, asappreciated by one of ordinary skill in the art, two adjacent groups onan aromatic system may be fused together to form a ring structure. Thefused ring structure may contain heteroatoms and may be optionallysubstituted with one or more groups. It should additionally be notedthat saturated carbons of such fused groups (i.e. saturated ringstructures) can contain two substitution groups.

“Haloaloxy” means an —OR′ group where R′ is haloalkyl as defined herein,e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.

“Haloalkoxyalkyl” means an alkyl group, as defined herein, substitutedwith one, two, or three haloalkoxy, as defined herein.

“Halogen” or “halo” means fluoro, chloro, bromo and iodo.

“Haloalkenyl means an alkenyl group, as defined herein, substituted withone or more halogens, specifically one to five halo atoms.

“Haloalkyl” means an alkyl group, as defined herein, substituted withone or more halogens, specifically one to five halo atoms.Representative examples includes 2,2-difluoroethyl, trifluoromethyl, and2-chloro-1-fluoroethyl, and the like.

“Heteroaryl” means a monocyclic, fused bicyclic, or fused tricyclic,monovalent radical of 5 to 14 ring atoms containing one or more,specifically one, two, three, or four ring heteroatoms independentlyselected from —O—, —S(O)_(n)— (n is 0, 1, or 2), —N—, —N(R^(x))—, andthe remaining ring atoms being carbon, wherein the ring comprising amonocyclic radical is aromatic and wherein at least one of the fusedrings comprising a bicyclic or tricyclic radical is aromatic. One or tworing carbon atoms of any nonaromatic rings comprising a bicyclic ortricyclic radical may be replaced by a —C(O)—, —C(S)—, or —C(═NH)—group. R^(x) is hydrogen, alkyl, hydroxy, alkoxy, acyl, oralkylsulfonyl. Fused bicyclic radical includes bridged ring systems.Unless stated otherwise, the valency may be located on any atom of anyring of the heteroaryl group, valency rules permitting. In particular,when the point of valency is located on the nitrogen, R^(x) is absent.More specifically, the term heteroaryl includes, but is not limited to,1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl,imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1H-indolyl(including, for example, 2,3-dihydro-1H-indol-2-yl or2,3-dihydro-1H-indol-5-yl, and the like), isoindolyl, indolinyl,isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl,cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl,phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl,tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl,tetrahydroisoquinolinyl (including, for example,tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like),pyrrolo[3,2-c]pyridinyl (including, for example,pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like),benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl,benzothienyl, and the derivatives thereof, or N-oxide or a protectedderivative thereof.

“Hetereoarylalkyl” means an alkyl group substituted with one or twoheteroaryl group(s) as defined herein.

“Heterocycloalkyl” means a saturated or partially unsaturated monovalentmonocyclic group of 3 to 8 ring atoms or a saturated or partiallyunsaturated monovalent fused bicyclic group of 5 to 10 ring atoms inwhich one or more, specifically one, two, three, or four ringheteroatoms independently selected from —O—, —S(O)_(n)— (n is 0, 1, or2), —N═, —N(R^(y))— (where R^(y) is hydrogen, alkyl, hydroxy, alkoxy,acyl, or alkylsulfonyl), the remaining ring atoms being carbon.Heterocycloalkyl is also known as heterocycle. One or two ring carbonatoms may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Fusedbicyclic radical includes bridged ring systems. Unless otherwise stated,the valency of the group may be located on any atom of any ring withinthe radical, valency rules permitting. In particular, when the point ofvalency is located on a nitrogen atom, R^(y) is absent. Morespecifically the term heterocycloalkyl includes, but is not limited to,azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl,piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl,tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl,perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl,isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl,isothiazolidinyl, octahydroindolyl, octahydroisoindolyl,decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and thederivatives thereof and N-oxide or a protected derivative thereof.

“Heterocycloalkylalkyl” means an alkyl group, as defined herein,substituted with one or two heterocycloalkyl group(s), as definedherein.

“Hydroxyalkyl” means an alkyl radical, as defined herein, substitutedwith at least one, specifically one, two, or three, hydroxy group(s),provided that if two hydroxy groups are present they are not both on thesame carbon atom. Representative examples include, but are not limitedto, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, specifically 2-hydroxyethyl,2,3-dihydroxypropyl, or 1-(hydroxymethyl)-2-hydroxyethyl, and the like.

“Hydroxyamino” means a —NH(OH) group.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that withrespect to any molecule described as containing one or more optionalsubstituents, only sterically practical and/or synthetically feasiblecompounds are meant to be included. “Optionally substituted” refers toall subsequent modifiers in a term. So, for example, in the term“optionally substituted aryl C₁₋₈ alkyl,” both the “C₁₋₈ alkyl” portionand the “aryl” portion of the molecule may or may not be substituted. Alist of exemplary optional substitutions is presented below in thedefinition of “substituted.”

“Optionally substituted alkyl” means an alkyl radical, as definedherein, optionally substituted with one or more group(s), specificallyone, two, three, four, or five groups, independently selected fromalkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, cyano,cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy,carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)₀₋₂—,alkenyl-S(O)₀₋₂—, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl-NR^(c)— (where R^(c) is hydrogen,alkyl, optionally substituted alkenyl, optionally substituted alkynyl,hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy,alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino,alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and—C(O)NR^(a)R^(b) (where R^(a) and R^(b) are independently hydrogen,alkyl, optionally substituted alkenyl, optionally substituted alkynyl,hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).

“Optionally substituted alkenyl” means an alkenyl radical, as definedherein, optionally substituted with one or more group(s), specificallyone, two, or three groups, independently selected from alkylcarbonyl,alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, cyano,cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy,carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)₀₋₂—,alkenyl-S(O)₀₋₂—, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl-NR^(c)— (where R^(c) is hydrogen,optionally substituted alkyl, optionally substituted alkynyl, hydroxy,alkoxy, or alkenyloxy), alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl,alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino,dialkylaminocarbonylamino, alkoxyalkyloxy, and —C(O)NR^(a)R^(b) (whereR^(a) and R^(b) are independently hydrogen, optionally substitutedalkyl, alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, oralkenyloxy).

“Optionally substituted aryl” means an aryl group, as defined herein,which is optionally substituted with one, two, three, four, of fivegroups selected from halo, haloalkyl, haloalkoxy, hydroxy, lower alkyl,lower alkenyl, lower alkynyl, alkoxy, carboxy, carboxy ester, amino,alkylamino, dialkylamino, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted heteroaryl,—C(O)NR′R″ (where R′ is hydrogen or alkyl and R″ is hydrogen, alkyl,aryl, heteroaryl, or heterocycloalkyl), —NR′C(O)R″ (where R′ is hydrogenor alkyl and R″ is alkyl, aryl, heteroaryl, or heterocycloalkyl), and—NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Optionally substituted heteroaryl” means a heteroaryl group, as definedherein, optionally substituted with one, two, three, four, or fivegroups selected from halo, haloalkyl, haloalkoxy, lower alkyl, loweralkenyl, lower alkynyl, alkoxy, hydroxy, oxo (valency rules permitting),carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,heteroaryl, optionally substituted aryl, —C(O)NR′R″ (where R′ ishydrogen or alkyl and R″ is hydrogen, alkyl, aryl, heteroaryl, orheterocycloalkyl), —NR′C(O)R″ (where R′ is hydrogen or alkyl and R″ isalkyl, aryl, heteroaryl, or heterocycloalkyl), and —NHS(O)₂R′ (where R′is alkyl, aryl, or heteroaryl).

“Optionally substituted heterocycloalkyl” means a heterocycloalkyl, asdefined herein, optionally substituted with one, two, three, four, orfive groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo,oxime, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, optionallysubstituted cycloalkyl, heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl,carboxy, carboxy ester, —C(O)NR′R″ (where R′ is hydrogen or alkyl and R″is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), —NR′C(O)R″(where R′ is hydrogen or alkyl and R″ is alkyl, aryl, heteroaryl, orheterocycloalkyl), amino, alkylamino, dialkylamino, and —NHS(O)₂R′(where R′ is alkyl, aryl, or heteroaryl).

“Preventing” or “prevention” of a disease, disorder, or syndromeincludes inhibiting the disease from occurring in a human, i.e. causingthe clinical symptoms of the disease, disorder, or syndrome not todevelop in an animal that may be exposed to or predisposed to thedisease, disorder, or syndrome but does not yet experience or displaysymptoms of the disease, disorder, or syndrome.

“Treating” or “treatment” of a disease, disorder, or syndrome, as usedherein, includes (i) inhibiting the disease, disorder, or syndrome,i.e., arresting its development; and (ii) relieving the disease,disorder, or syndrome, i.e., causing regression of the disease,disorder, or syndrome. As is known in the art, adjustments for systemicversus localized delivery, age, body weight, general health, sex, diet,time of administration, drug interaction and the severity of thecondition may be necessary, and will be ascertainable with routineexperimentation by one of ordinary skill in the art. Treatment as aprophylactic measure is also included. Treatment includes combinationtreatments and therapies, in which two or more treatments or therapiesare combined, for example, sequentially or simultaneously. Examples oftreatments and therapies include, but are not limited to, chemotherapy(the administration of active agents, including, e.g., drugs, antibodies(e.g., as in immunotherapy), prodrugs and the like), surgery; radiationtherapy; and gene therapy.

“Co-administration” or “combined administration” or the like as utilizedherein are meant to include modes of administration of the selectedactive, therapeutic agents to a single patient, and are intended toinclude treatment regimens in which the agents are not necessarilyadministered by the same route of administration or at the same time.Co-administration can also include delivery of the active ingredients ina “fixed combination,” e.g. a Compound of Formulae I and ananti-inflammatory agent, which are both administered to a patientsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that the active ingredients, e.g. aCompound of Formula I and a second active agent, for example, ananti-inflammatory agent as exemplified below, are both administered to apatient as separate entities either simultaneously, concurrently orsequentially with no specific time limits, such that the administrationprovides therapeutically effective levels of the combination of activeagents in the body of the patient.

For the purposes of the present invention, the terms “Subject” or“Patient” which are used interchangeably herein, include humans andother animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. In a specific embodiment the patient is a mammal, and in amore specific embodiment the patient is human.

“Hypersensitivity and/or disorders related to immune hypersensitivitygenerally refer to allergic forms of a disease exemplified but notlimited to: asthma, rhinitis, conjunctivitis, rhinoconjuctivitis,dermatitis, urticaria, food hypersensitivity, drug hypersensitivity,insect sting or bite hypersensitivity, and anaphylaxis. In particular,hypersensitivity also includes any type of allergy.

As used herein, “allergy” encompasses “allergic hypersensitivity” and isto be understood as suggested by Johansson et al. 2001, Allergy56:813-824 and Johannson et al. 2004, J. Allergy Clin. Immunol. 113(5)832-835. Unless otherwise indicated, the application follows thenomenclature for allergy as set forth therein. Allergy or allergichypersensitivity is a hypersensitivity reaction initiated by immunologicmechanisms in response to a substance (allergen), often in a geneticallypredisposed individual (atopy). Allergy can be antibody- orcell-mediated. In most patients, the antibody typically responsible foran allergic reaction belongs to the IgE isotype (see “antibodies”) andthese patients may be said to suffer from IgE-mediated allergy (type-Iallergy). It must be noted that not all IgE-mediated allergic reactionsoccur in atopic subjects. In non IgE-mediated allergy, the antibody maybelong to the IgG isotype. Thus, within the meaning of the application,“allergy” refers to both, IgE-mediated allergy (type-I allergy) and nonIgE-mediated allergy. IgE-mediated allergy is preferably addressed bythe invention. Therefore, in the context of the invention allergypreferably refers to IgE-mediated allergy. Allergies are classifiedaccording to the source of the antigen evoking the hypersensitivereaction. In one embodiment allergy is selected from (a) food allergy,(b) drug allergy, (c) house dust allergy, (d) insect venom or biteallergy, and (e) pollen allergy. Alternatively, allergies are classifiedbased on the major symptoms of the hypersensitive reaction. Thus, inanother embodiment allergy refers to any allergic form of a diseaseincluding, but not limited to: asthma, rhinitis, conjunctivitis,rhinoconjuctivitis, dermatitis, urticaria and anaphylaxis.

As used herein, “type-I allergy”: the terms “type-I allergy” and“IgE-mediated allergy” are used interchangeably and relate toIgE-mediated hypersensitivities to allergens. Preferred embodiments ofthe invention relate to IgE-mediated allergy exemplified by pollenallergy (hay fever); house dust allergy; food allergy; drug allergy;insect venom or bite allergy, preferably bee venom allergy; and animalallergy, preferably cat allergy.

As used herein, “hay fever” is encompassed by a typical form of anIgE-mediated allergy (type-I allergy) against pollen which may compriserhinitis, conjunctivitis and/or asthma, wherein asthma preferably occursin chronic forms of hay fever.

As used herein, “atopy”, “atopic diseases”: Atopy is a personal orfamilial tendency to produce IgE antibodies in response to low doses ofallergens, usually proteins, and to develop typical symptoms such asasthma, rhinoconjunctivitis, or eczema/dermatitis. The firstmanifestations of atopy in a child are often allergic symptoms, such asdiarrhea, wheezing, and skin rashes, and only later can the responsibleIgE antibody be detected. Allergic symptoms in a typical atopicindividual may be referred to as atopic. In one embodiment of theinvention hypersensitivity is an atopic disease, preferably an atopicdisease selected from the group consisting of (a) atopic asthma, (b)atopic eczema, (c) atopic IgE-mediated allergy, preferably pollenallergy (hay fever), house dust allergy or house dust mite allergy. Inone embodiment the application relates to IgE-mediated allergy ingeneral, irrespective of whether or not said IgE-mediated allergy isregarded as atopic or non atopic allergy. However, specificallypreferred embodiments of the invention relate to atopic allergy,preferably to IgE-mediated atopic allergy.

As used herein, “rhinitis” relates to hypersensitivity symptoms from thenose, for example, itching, sneezing, increased secretion, and blockage.Rhinitis relates to non-allergic as well as allergic, i.e.immunologically mediated, rhinitis. Preferred embodiments of theinvention relate to allergic rhinitis, preferably to IgE-mediated andnon IgE-mediated forms of allergic rhinitis. Specifically preferredembodiments relate to IgE-mediated allergic rhinitis.

As used herein, the term “conjunctivitis” relates to primarilyirritations of the eye which can be of allergic as well as non-allergicorigin, wherein allergic conjunctivitis encompasses IgE-mediated and nonIgE-mediated allergic conjunctivitis. Allergic conjunctivitis,especially IgE mediated allergic conjunctivitis is commonly accompaniedby allergic rhinitis, so this disorder is appropriately termed allergicrhinoconjuctivitis. Besides IgE-mediated conjunctivitis, contactallergic conjunctivitis involving TH1 mechanisms occurs. Non-allergicconjunctivitis also often accompanies non-allergic rhinitis. In someembodiments of the invention, conjunctivitis may relate to allergicconjunctivitis, including IgE-mediated and non IgE-mediated forms ofallergic conjunctivitis. In one embodiment, the present inventionrelates to IgE-mediated allergic conjunctivitis. Other embodimentsrelate to IgE-mediated allergic rhinoconjunctivitis.

As used herein, “asthma” or asthma bronchiale is a chronic respiratorydisease due to inflammation of the air passages in the lungs and affectsthe sensitivity of the nerve endings in the airways so they becomeeasily irritated. Asthma is intended to encompass bronchial asthma,allergic asthma, intrinsic asthma, and occupational asthma. In an asthmaattack, the lining of the passages swell causing the airways to narrowand reducing the flow of air in and out of the lungs. Asthma can occurin a intermittent form (2 attacks per week or less during daytime, 2attacks per month or less at night), in persistent form (permanentattacks during daytime, frequent attacks at night) and in anyintermediate form. Within the meaning of the present invention, the termasthma may relate to non-allergic as well as to allergic asthma. In someembodiments of the invention, asthma may relate to allergic asthma,including IgE-mediated and non IgE-mediated forms of asthma. Otherembodiments relate to IgE-mediated allergic asthma, for example, toatopic asthma.

As used herein, “atopic asthma” includes IgE-mediated form of asthma inpatients with a genetic predisposition which often occurs in conjunctionwith atopic eczema and IgE-mediated allergies, for example pollenallergy (hay fever), house dust or dust mite.

As used herein, “dermatitis” relates to local inflammation of the skinand encompasses, besides other forms, “eczema” and “contact dermatitis”.In some embodiments of the invention, dermatitis may encompass eczemaand contact dermatitis.

As used herein, the term “eczema” relates to the atopiceczema/dermatitis syndrome (AEDS), describing an aggregation of severalskin diseases with certain clinical characteristics in common involvinga genetically determined skin barrier defect. This geneticallydetermined target organ sensitivity constitutes the basis for eczema. Inchildren and young adults of the atopic constitution, the underlyinginflammation is dominated by an IgE-antibody associated reaction (atopiceczema). In chronic cases, the inflammation seems to be less influencedby IgE antibody, and the dominating cells in biopsies are lymphocytes.Eczema relates to non-allergic eczema and allergic eczema. In someembodiments of the invention, eczema includes allergic eczema includingatopic (IgE-mediated) eczema and non-atopic forms of eczema. In someembodiments, the invention relates to atopic (IgE-mediated) eczema.

As used herein, the term “contact dermatitis” relates to localinflammatory reaction in the skin caused by close contact with lowmolecular weight chemicals or irritants. Contact dermatitis can be ofallergic as well as non-allergic nature. Allergic contact dermatitis ismediated by immunological mechanisms, predominantly TH1 lymphocytes.Typical allergens acting as haptens and causing allergic contactdermatitis can include: nickel, chromium ions, fragrances,preservatives, and urushiol, from the poison ivy plant among others.Exposure can occur through oral uptake, so-called systemic allergiccontact dermatitis. A subgroup of contact dermatitis, protein contactdermatitis, is an IgE-associated reaction caused by absorption ofproteins through damaged skin. In some embodiments of the invention,contact dermatitis includes allergic contact dermatitis. Furtherembodiments relate to protein contact dermatitis.

As used herein, the term “urticaria” relates to a non inflammatoryreaction in the skin caused by an irritant or allergen and includesnon-allergic urticaria as well as allergic urticaria. Allergic urticariais mediated by immunological mechanisms, which commonly is IgE-mediatedbut can also be immune complex-associated. Urticaria can also developlocally after topical contact with the allergen, as occurs on the handsof a person with latex allergy wearing latex gloves or in a person withdog allergy licked by a dog. In some embodiments of the invention, theterm urticaria relates to allergic urticaria, most preferablyIgE-mediated allergic urticaria.

As used herein, “food hypersensitivity” includes conditions relating toadverse reaction to food, which can be of non-allergic as well asallergic nature. Allergic food hypersensitivities can be IgE-mediatedand are referred to as food allergies. Severe, generalized allergicreactions to food can involve anaphylaxis. In some embodiments of theinvention, food hypersensitivity can include food allergies, preferablyan IgE-mediated food allergy.

As used herein, the term “drug hypersensitivity” relates tohypersensitive reactions of the body towards drugs which can be ofnon-allergic as well as of allergic nature. When immunologic mechanismshave been shown, either antibody or cell mediated, the reactions arereferred to as drug allergy. Drug allergies can be mediated by IgE. Insome embodiments of the invention, drug hypersensitivity, encompassesdrug allergies, for example, IgE-mediated drug allergies.

As used herein, the terms “insect sting hypersensitivity” or “insectbite hypersensitivity” relate to hypersensitive reactions towards insectvenom and saliva which can be of non-allergic as well as allergicnature. Insect sting hypersensitivity or insect bite hypersensitivitymediated by an immunologic mechanism is referred to as venom or salivaallergy, as in bee venom allergy. The large quantity of venom allergenin a sting is comparable with years of inhaled pollen allergen. Thishigh-dose sensitization probably explains why there is no need for agenetic predisposition for developing such an allergy. In someembodiments of the invention, “insect sting hypersensitivity” or “insectbite hypersensitivity” relate to venom allergy, for example,IgE-mediated venom allergy, including, but not limited to, IgE mediatedinsect (e.g. bees, wasps, mosquitoes, and ants) venom allergy.

As used herein, the term “anaphylaxis” refers to a severe,life-threatening, generalized or systemic hypersensitive reaction. Thereaction usually develops gradually, most often starting with itching ofthe gums/throat, the palms, or the soles, and local urticaria;developing to a multiple organ reaction often dominated by severeasthma; and culminating in hypotension and shock. Hypotension and severebronchospasm do not have to be present for a reaction to be classifiedas anaphylaxis. Anaphylaxis can be of non-allergic as well as ofallergic nature. Allergic anaphylaxis involves an immunologic mechanismlike an IgG immune complex, complement related, or immune cell-mediatedmechanism. Anaphylaxis preferably relates to an anaphylactic reactionmediated by IgE antibodies (IgE-mediated anaphylaxis), most preferablyto peanut-induced food anaphylaxis or bee venom-induced anaphylaxis.

As used herein, the term “allergen” refers to a substance causingallergy. Preferred allergens are allergens disclosed in Shough, H. etal., REMINGTON'S PHARMACEUTICAL SCIENCES, 19th edition, (Chap. 82), MackPublishing Company, Mack Publishing Group, Easton, Pa. (1995), theentire contents of which is hereby incorporated by reference. Allergensserve as antigens in vertebrate animals. The term “allergen”, as usedherein, also refers to “allergen extracts” and “allergenic epitopes.” Insome embodiments, allergens include: pollens (e.g. grass, ragweed, birchand mountain cedar); house dust and dust mites; mammalian epidermalallergens and animal danders; mold and fungus; insect bodies and insectvenom; feathers; food; and drugs (e.g. penicillin).

As used herein, the term “allergy inducing solution” can include asolution containing a biological and/or a chemical agent capable ofinducing an allergic reaction in a subject. Biological agents caninclude allergens, for example, pollens (e.g. grass, ragweed, birch andmountain cedar); house dust and dust mites; mammalian epidermalallergens and animal danders; mold and fungus; insect bodies and insectvenom; feathers and the like, generally, from a living organism.Chemical agents can include food allergens; and drugs (e.g. iodine,silver nitrate, MSG, preservatives, or antibiotics). In someembodiments, allergy inducing solutions can contain mixtures ofdifferent grasses, preferably of orchard grass, velvet grass, rye grass,timothy grass, Kentucky blue grass and/or Meadow fescue for example,mixtures of grasses, cereals, different trees and/or animal hair.Allergy inducing solutions can be prepared in physiological saline andcan be preserved by addition of 0.1%-1.0% phenol or thimerosal.

As used herein, the term “allergen extracts” includes components of usedfor conjunctival, nasal and bronchial challenges. Such allergen extractsare commercially available and methods for producing such extracts arewell-known. In some embodiments, single allergen extracts can be used toinduce an allergic reaction when implanted, injected, contacted orotherwise exposed to a test subject. In some embodiments, the allergenextracts are provided in an allergy inducing solution comprising asingle allergen extract which can be prepared from, for example, treespecies or a grass species, most preferably selected from the groupconsisting of alder, ash, birch, hazel, orchard grass, velvet grass, ryegrass, timothy grass, Kentucky blue grass, Meadow fescue, Bermuda grass,ragweed, rye and wheat; epithelia of different animal species,preferably epithelia from an animal species selected from the groupconsisting of cat, dog and horse; molds, exemplary molds can include:Aspergillus sp., Candida sp., Alternaria Sp., and Saccharomyces Sp.; andmite species, including, but not limited to: Dermatophagoides farinae,Dermatophagoides pteronyssinus and Acarus siro. Allergen extractscomprising allergen mixtures can also be used in allergy inducingsolutions.

As used herein, “antibody”: As used herein, the term “antibody” refersto molecules belonging to the class of immunoglobulins which are capableof binding an epitope or antigenic determinant.

As used herein, the term “antigen” refers to a molecule capable of beingbound by an antibody or a T-cell receptor (TCR) if presented by MHCmolecules. The term “antigen”, as used herein, also encompasses T-cellepitopes. An antigen is additionally capable of being recognized by theimmune system and/or being capable of inducing a humoral immune responseand/or cellular immune response leading to the activation of B- and/orT-lymphocytes. Antigens as used herein may also be mixtures of severalindividual antigens.

As used herein, the term “epitope” refers to continuous or discontinuousportions of a polypeptide having antigenic or immunogenic activity in ananimal, preferably a mammal, and most preferably in a human.

As used herein, “Compound A,” which is a compound of Formula I and ofTable I, i.e.4-[1-(5-methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one,means the structure:

“Therapeutically effective amount” is an amount of a compound of theinvention, that when administered to a patient, ameliorates a symptom ofthe disease. The amount of a compound of the invention which constitutesa “therapeutically effective amount” will vary depending on thecompound, the disease state and its severity, the age of the patient tobe treated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art having regardto their knowledge and to this disclosure.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. It is understood thatthe pharmaceutically acceptable salts are non-toxic. Additionalinformation on suitable pharmaceutically acceptable salts can be foundin Remington's Pharmaceutical Sciences, 17^(th) ed., Mack PublishingCompany, Easton, Pa., 1985, which is incorporated herein by reference orS. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 both of which are incorporated herein by reference.

Examples of pharmaceutically acceptable acid addition salts includethose formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like; as wellas organic acids such as acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylicacid and the like.

Examples of a pharmaceutically acceptable base addition salts includethose formed when an acidic proton present in the parent molecule isreplaced by a metal ion, such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Specific salts are the ammonium, potassium, sodium, calcium,and magnesium salts. Salts derived from pharmaceutically acceptableorganic non-toxic bases include, but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins. Examples of organic bases include isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

“Prodrug” refers to compounds that are transformed (typically rapidly)in vivo to yield the active ingredient of the above formulae, forexample, by hydrolysis in blood. Common examples of a prodrug include,but are not limited to, ester and amide forms of a compound having anactive form bearing a carboxylic acid moiety. Examples ofpharmaceutically acceptable esters of the compounds of this inventioninclude, but are not limited to, alkyl esters (for example with betweenabout one and about six carbons) the alkyl group is a straight orbranched chain. Acceptable esters also include cycloalkyl esters andarylalkyl esters such as, but not limited to benzyl. Examples ofpharmaceutically acceptable amides of the compounds of this inventioninclude, but are not limited to, primary amides, and secondary andtertiary alkyl amides (for example with between about one and about sixcarbons).

“Metabolite” refers to the break-down or end product of a compound orits salt produced by metabolism or biotransformation in the animal orhuman body; for example, biotransformation to a more polar molecule suchas by oxidation, reduction, or hydrolysis, or to a conjugate (seeGoodman and Gilman, “The Pharmacological Basis of Therapeutics” 8.sup.thEd., Pergamon Press, Gilman et al. (eds), 1990 for a discussion ofbiotransformation). As used herein, the metabolite of a compound of theinvention or its salt may be the biologically active form of thecompound in the body. In one example, a prodrug may be used such thatthe biologically active form, a metabolite, is released in vivo. Inanother example, a biologically active metabolite is discoveredserendipitously, that is, no prodrug design per se was undertaken. Anassay for activity of a metabolite of a compound of the presentinvention is known to one of skill in the art in light of the presentdisclosure.

“Treating” or “treatment” of a disease, disorder, or syndrome, as usedherein, includes (i) preventing the disease, disorder, or syndrome fromoccurring in a human, i.e. causing the clinical symptoms of the disease,disorder, or syndrome not to develop in an animal that may be exposed toor predisposed to the disease, disorder, or syndrome but does not yetexperience or display symptoms of the disease, disorder, or syndrome;(ii) inhibiting the disease, disorder, or syndrome, i.e., arresting itsdevelopment; and (iii) relieving the disease, disorder, or syndrome,i.e., causing regression of the disease, disorder, or syndrome. As isknown in the art, adjustments for systemic versus localized delivery,age, body weight, general health, sex, diet, time of administration,drug interaction and the severity of the condition may be necessary, andwill be ascertainable with routine experimentation by one of ordinaryskill in the art.

Compounds

The present invention relates to compounds useful as inhibitors ofallergic reactions. Compounds of the present invention are described bythe following chemical Formula I:

or a pharmaceutically acceptable salt, solvate or prodrug thereof,whereinR₂ is each independently C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy,alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀aralkyl, aralkyloxy, C₄₋₁₀ heteroaryl, or C₄₋₁₀ heteroaralkyl, whereineach C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl,aralkyloxy, C₄₋₁₀ heteroaryl, or C₄₋₁₀ heteroaralkyl optionallyincluding 1-3 substituents independently selected from Q₁ or Q₂;R₃ is each independently, hydrogen, halo, OH, —ON, —NO₂, —N═O, —NHOQ₁,—OQ₁, —SOQ₁, —SO₂Q₁, —SON(Q₁)₂, —SO₂N(Q₁)₂, —N(Q₁)₂, —C(O)OQ₁, —C(O)Q₁,—C(O)N(Q₁)₂, —C(═NQ₁)NQ₁-, —NQ₁C(═NQ₁)NQ₁-, —C(O)N(Q₁)(OQ₁),—N(Q₁)C(O)-Q₁, —N(Q₁)C(O)N(Q₁)₂, —N(Q₁)C(O)O-Q₁, —N(Q₁)SO₂Q₁,—N(Q₁)SOQ₁, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy,C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl,aralkyloxy, C₄₋₁₀ heteroaryl, or C₄₋₁₀ heteroaralkyl, wherein each C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl,C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, or C₄₋₁₀ heteroaralkyl optionally substituted with 1-3substituents independently selected from Q₁ or Q₂;each Q₁ is independently hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, alkoxy,alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ arylalkyl, aralkyloxy,C₄₋₁₀ heterocyclic, or C₄₋₁₀ heteroaryl ring, each optionally including1-3 substituents independently selected from Q₂;each Q₂ is halo, haloalkyl, oxo, oxime, azido, amino, amido, cyano, CN,NO₂, CF₃, OCF₃, OH, —COOH or C₁-C₄ alkyl optionally substituted with 1-3of halo, oxo, oxime, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)₃H, —NH₂, or—COOH.The R₂ Variable

In some embodiments, R₂ is each independently C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, or C₄₋₁₀ heteroaralkyl, wherein each C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, or C₄₋₁₀ heteroaralkyl optionally substituted with 1-3substituents independently selected from hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl,C₄₋₁₀ aryl, C₄₋₁₀ arylalkyl, aralkyloxy, or C₄₋₁₀ heteroaryl, whereineach C₁₋₈ alkyl, C₂₋₈ alkenyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ arylalkyl, aralkyloxy, or C₄₋₁₀heteroaryl optionally including 1-3 substituents independently selectedfrom halo, oxo, oxime, azido, amino, amido, cyano, CN, NO₂, CF₃, OCF₃,OH, —COOH or C₁-C₄ alkyl optionally substituted with 1-3 of halo, oxo,oxime, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)₃H, —NH₂, or —COOH. Inanother embodiment, R₂ is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₄₋₁₀ cycloalkyl,C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, or C₄₋₁₀ heteroaryl. In anotherembodiment, R₂ is C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl or C₄₋₁₀heteroaryl. In some embodiments, R₂ is a C₄₋₁₀ heterocycloalkyl or C₄₋₁₀heteroaryl. In some embodiments, R₂ is a C₄₋₁₀ heteroaryl.

In some embodiments, R₂ is each independently C₄₋₁₀ alkyl, C₄₋₁₀alkenyl, C₄₋₁₀ alkynyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, or C₄₋₁₀ heteroaralkyl, wherein each C₄₋₁₀ alkyl, C₄₋₁₀alkenyl, C₄₋₁₀ alkynyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, or C₄₋₁₀ heteroaralkyl optionally substituted with 1-3substituents independently selected from hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl,C₄₋₁₀ aryl, C₄₋₁₀ arylalkyl, aralkyloxy, or C₄₋₁₀ heteroaryl, whereineach C₁₋₈ alkyl, C₂₋₈ alkenyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ arylalkyl, aralkyloxy, or C₄₋₁₀heteroaryl optionally including 1-3 substituents independently selectedfrom halo, oxo, oxime, azido, amino, amido, cyano, CN, NO₂, CF₃, OCF₃,OH, —COOH or C₁-C₄ alkyl optionally substituted with 1-3 of halo, oxo,oxime, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)₃H, —NH₂, or —COOH.

In another embodiment, R₂ is C₄₋₈ alkyl, C₄₋₈ alkenyl, C₄₋₁₀ cycloalkyl,C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, or C₄₋₁₀ heteroaryl. In anotherembodiment, R₂ is C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl or C₄₋₁₀heteroaryl. In some aspects, R₂ is a C₄₋₁₀ heterocycloalkyl or a C₄₋₁₀heteroaryl. In some embodiments, R₂ is a C₄₋₁₀ heteroaryl. In someaspects, R₂ is piperidine, azabenzimidazole, benzoimidazolyl,benzofuryl, benzofurazanyl, benzopyrazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl,carbolinyl, chromanyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuryl, isochromanyl,isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl,oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl,pyridinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl,1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl,morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuryl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuryl,dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydropyrimidinyl,dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl,dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl,dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuryl,tetrahydrothienyl, tetrahydroquinolinyl, 2,3-dihydrobenzofuryl,2,3-dihydrobenzo-1,4-dioxinyl, imidazo(2,1-b)(1,3)thiazole, andbenzo-1,3-dioxolyl. pyridine-N-oxide, 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, N-methyl-piperidinyl, N-ethyl-piperidinyl,N-propyl-piperidinyl, hexahydrothiopyranyl, azepanyl, methylazepanyl,tetrahydropyranyl, piperidinylmethyl, pyridinyl, pyridinylmethyl,tetrahydrothiopyranyl, dioxolanylmethyl, dioxanylmethyl.N-isopropyl-piperidinyl, N-butyl-piperidinyl, N-pentyl-piperidinyl,N-hexylpiperidinyl, N-cyclohexyl-piperidinyl, N-acetyl-piperidinyl,N-benzyl-piperidinyl. In some embodiments, R₂ is pyridine.

In some embodiments, R₂ is selected from:

The R₃ Variable

In some embodiments, R₃ is each independently hydrogen, halo, OH, —CN,—NO₂, —N═O, —NHOQ₁, —OQ₁, —SOQ₁, —SO₂Q₁, —SON(Q₁)₂, —SO₂N(Q₁)₂, —N(Q₁)₂,—C(O)OQ₁, —C(O)Q₁, —C(O)N(Q₁)₂, —C(═NQ₁)NQ₁-, —NQ₁C(═NQ₁)NQ₁-,—C(O)N(Q₁)(OQ₁), —N(Q₁)C(O)-Q₁, —N(Q₁)C(O)N(Q₁)₂, —N(Q₁)C(O)O-Q₁,—N(Q₁)SO₂Q₁, —N(Q₁)SOQ₁, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy,alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀aralkyl, aralkyloxy, C₄₋₁₀ heteroaryl, C₄₋₁₀ heteroaralkyl, wherein eachC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl,aralkyloxy, C₄₋₁₀ heteroaryl, C₄₋₁₀ heteroaralkyl optionally substitutedwith 1-3 substituents independently selected from halo, haloalkyl, oxo,oxime, azido, amino, amido, cyano, CN, NO₂, CF₃, OCF₃, OH, —COOH orC₁-C₄ alkyl optionally substituted with 1-3 of halo, oxo, oxime, —CN,—NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)₃H, —NH₂, or —COOH.

each Q₁ is independently hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, alkoxy,alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ arylalkyl, aralkyloxy,C₄₋₁₀ heterocyclic, or C₄₋₁₀ heteroaryl ring, each optionally including1-3 substituents independently selected from Q₂;

each Q₂ is halo, haloalkyl, oxo, oxime, azido, amino, amido, cyano, CN,NO₂, CF₃, OCF₃, OH, —COOH or C₁-C₄ alkyl optionally substituted with 1-3of halo, oxo, oxime, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)₃H, —NH₂, or—COOH. In some embodiments, R₃ is each independently selected from H,C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl,aralkyloxy, C₄₋₁₀ heteroaryl, or C₄₋₁₀ heteroaralkyl. In anotherembodiment, R₃ is H or C₁₋₈ alkyl. In some embodiments, R₃ is hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, 2-ethylpropyl,or cyclohexyl. In some embodiments, R₃ is hydrogen or methyl.

In some embodiments, R₃ is each independently selected from H, C₁₋₈alkyl, C₁₋₈ alkenyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, C₄₋₁₀ heteroaralkyl.

Formula Ia

The present invention relates to compounds useful as inhibitors ofallergic reactions. Compounds of the present invention are described bythe following chemical Formula Ia:

or a pharmaceutically acceptable salt, solvate or prodrug thereof,wherein

In some embodiments, R₃ is each independently hydrogen, halo, OH, —CN,—NO₂, —N═O, —NHOQ₁, —OQ₁, —SOQ₁, —SO₂Q₁, —SON(Q₁)₂, —SO₂N(Q₁)₂, —N(Q₁)₂,—C(O)OQ₁, —C(O)Q₁, —C(O)N(Q₁)₂, —C(═NQ₁)NQ₁-, —NQ₁C(═NQ₁)NQ₁-,—C(O)N(Q₁)(OQ₁), —N(Q₁)C(O)-Q₁, —N(Q₁)C(O)N(Q₁)₂, —N(Q₁)C(O)O-Q₁,—N(Q₁)SO₂Q₁, —N(Q₁)SOQ₁, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy,alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀aralkyl, aralkyloxy, C₄₋₁₀ heteroaryl, C₄₋₁₀ heteroaralkyl, wherein eachC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl,aralkyloxy, C₄₋₁₀ heteroaryl, C₄₋₁₀ heteroaralkyl optionally substitutedwith 1-3 substituents independently selected from halo, haloalkyl, oxo,oxime, azido, amino, amido, cyano, CN, NO₂, CF₃, OCF₃, OH, —COOH orC₁-C₄ alkyl optionally substituted with 1-3 of halo, oxo, oxime, —CN,—NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)₃H, —NH₂, or —COOH.

each Q₁ is independently hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, alkoxy,alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ arylalkyl, aralkyloxy,C₄₋₁₀ heterocyclic, or C₄₋₁₀ heteroaryl ring, each optionally including1-3 substituents independently selected from Q₂;

each Q₂ is halo, haloalkyl, oxo, oxime, azido, amino, amido, cyano, CN,NO₂, CF₃, OCF₃, OH, —COOH or C₁-C₄ alkyl optionally substituted with 1-3of halo, oxo, oxime, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)₃H, —NH₂, or—COOH. In some embodiments, R₃ is each independently selected from H,C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl,aralkyloxy, C₄₋₁₀ heteroaryl, or C₄₋₁₀ heteroaralkyl. In anotherembodiment, R₃ is H or C₁₋₈ alkyl. In some embodiments, R₃ is hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, 2-ethylpropyl,or cyclohexyl. In some embodiments, R₃ is hydrogen or methyl.

TABLE 1 Exemplary Compounds Of Formula I Compound Number Structure andFormula 1

  C₂₄H₂₂N₂OS 4-(1-Pyridin-3-ylmethyl-piperidin-4-ylidene)-4,9-dihydro-1-thia-benzo[f]azulen-10-one 2

  C₂₅H₂₄N₂OS 4-[1-(4-Methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 3

  C₂₅H₂₄N₂OS 4-[1-(6-Methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 4

  C₂₅H₂₄N₂OS 4-[1-(2-Methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 5

  C₂₄H₂₂N₂OS 4-(1-Pyridin-4-ylmethyl-piperidin-4-ylidene)-4,9-dihydro-1-thia-benzo[f]azulen-10-one 6

  C₂₅H₂₄N₂OS 4-[1-(3-Methyl-pyridin-4-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 7

  C₂₅H₂₄N₂OS 4-[1-(2-Methyl-pyridin-4-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 8

  C₂₅H₂₄N₂OS 4-[1-(6-Methyl-pyridin-2-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 9

  C₂₅H₂₄N₂OS 4-[1-(3-Methyl-pyridin-2-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 10

  C₂₅H₂₄N₂OS 4-[1-(4-Methyl-pyridin-2-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 11

  C₂₅H₂₄N₂OS 4-[1-(5-Methyl-pyridin-2-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 12

  Molecular Formula = C₂₅H₂₄N₂OS4-[1-(5-Methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one

In some embodiments, the present invention also includespharmaceutically acceptable addition salts of the compounds of FormulaI. The compounds of the present invention can be added to organic andinorganic acids to form these pharmaceutically acceptable additionsalts. Pharmaceutically acceptable addition salts of compounds ofFormula I are also part of the present invention. There is no limitationon the nature of these salts, provided that, when used for therapeuticpurposes, they are pharmaceutically acceptable, which, as is well knownin the art. For example, pharmaceutically acceptable salts can includesalts that are pharmaceutically acceptable acid addition salts. Examplesof these salts include: salts with an inorganic acid such ashydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid,perchloric acid, sulfuric acid or phosphoric acid; and salts with anorganic acid, such as methanesulfonic acid, trifluoromethanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,fumaric acid, oxalic acid, maleic acid, citric acid; and other mineraland carboxylic acids well known to those skilled in the art. The saltsare prepared by contacting the free base form with a sufficient amountof the desired acid to produce a salt in the conventional manner. Thefree base form differs from its salt forms somewhat in certain physicalproperties, such as solubility in polar solvents, but they areequivalent for purposes of the invention.

In some embodiments, the compound of Formula I can exist in unsolvatedas well as solvated forms, including hydrated forms. In general, thesolvated forms, with pharmaceutically acceptable solvents such as water,ethanol and the like are equivalent to the unsolvated form for purposesof the invention.

Compositions

In another embodiment, this invention provides pharmaceuticalcompositions comprising the above-described inventive compounds ofFormula I as an active ingredient. The pharmaceutical compositionsgenerally additionally comprise a pharmaceutically acceptable vehicle,diluent, excipient or carrier (collectively referred to herein asexcipient materials or non-active ingredient). The pharmaceuticalcompositions of the present invention possess utility in treatingallergic diseases and conditions, inflammation, ocular irritation, “dryeye” conditions (xeropthalmia), nasal congestion, respiratory airwayinflammation diseases such as asthma and the like diseases.

In some embodiments, the present invention discloses methods forpreparing pharmaceutical compositions comprising the inventive compoundsof Formula I as an active ingredient. In the pharmaceutical compositionsand methods of the present invention, the active ingredient willtypically be administered in admixture with suitable carrier materialssuitably selected with respect to the intended form of administration,i.e. oral tablets, capsules (either solid-filled, semi-solid filled orliquid filled), powders for constitution, oral gels, elixirs,dispersible granules, syrups, suspensions, sprays, liquid drops, washes,ointments, topical liposome formulations and the like, and consistentwith conventional pharmaceutical practices. For example, for oraladministration in the form of tablets or capsules, the active drugcomponent may be combined with any oral non-toxic pharmaceuticallyacceptable inert carrier, such as lactose, starch, sucrose, cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, talc,mannitol, ethyl alcohol (liquid forms) and the like. Moreover, whendesired or needed, suitable binders, lubricants, disintegrating agentsand coloring agents may also be incorporated in the mixture.

Suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethylcellulose, polyethylene glycol and waxes. Among thelubricants there may be mentioned for use in these dosage forms, boricacid, sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrants include starch, methylcellulose, guar gum and the like.Sweetening and flavoring agents and preservatives may also be includedwhere appropriate. Some of the terms noted above, namely disintegrants,diluents, lubricants, binders and the like, are discussed in more detailbelow.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects, i.e. antihistaminic activity and thelike. Suitable dosage forms for sustained release include layeredtablets containing layers of varying disintegration rates or polymericmatrices impregnated with the active components and shaped in tabletform or capsules containing such impregnated or encapsulated porouspolymeric matrices.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injections or addition of sweeteners and pacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the compounds of the present inventionwith for example suitable non-irritating excipients or carriers such ascocoa butter, polyethyleneglycol or a suppository wax, which are solidat ordinary temperatures but liquid at body temperature and therefore,melt while in a suitable body cavity and release the active componenttherein.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of Formula I may also be deliverable transdermally. Thetransdermal compositions may take the form of creams, lotions, aerosolsand/or emulsions and can be included in a transdermal patch of thematrix or reservoir type as are conventional in the art for thispurpose.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules) and the bioavailability of the drugsubstance. Recently, pharmaceutical formulations have been developedespecially for drugs that show poor bioavailability based upon theprinciple that bioavailability can be increased by increasing thesurface area i.e., decreasing particle size. For example, U.S. Pat. No.4,107,288 describes a pharmaceutical formulation having particles in thesize range from 10 to 1,000 nm in which the active material is supportedon a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684describes the production of a pharmaceutical formulation in which thedrug substance is pulverized to nanoparticles (average particle size of400 nm) in the presence of a surface modifier and then dispersed in aliquid medium to give a pharmaceutical formulation that exhibitsremarkably high bioavailability.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

One specific route of administration is oral, using a convenient dailydosage regimen that can be adjusted according to the degree of severityof the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the compoundof Formula I is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example, cellulosederivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, croscarmellose sodium, complexsilicates, and sodium carbonate, (e) solution retarders, as for exampleparaffin, (f) absorption accelerators, as for example, quaternaryammonium compounds, (g) wetting agents, as for example, cetyl alcohol,and glycerol monostearate, magnesium stearate and the like (h)adsorbents, as for example, kaolin and bentonite, and (i) lubricants, asfor example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the compound or compounds of Formula I in a certain part ofthe intestinal tract in a delayed manner. Examples of embeddedcompositions that can be used are polymeric substances and waxes. Theactive compounds can also be in microencapsulated form, if appropriate,with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Suchdosage forms are prepared, for example, by dissolving, dispersing, etc.,a compound(s) of Formula I, or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike; solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide; oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan; or mixtures of these substances, and the like, to thereby forma solution or suspension.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like. In some embodiments, the compositions may alsobe administered in the form of liposomes. Liposomes are generallyderived from phospholipids or other lipid substances, and are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolisable lipid capable of forming liposomes can be used. Thecompositions in liposome form may contain stabilisers, preservatives,excipients and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.Methods to form liposomes are known in the art, and in relation to thisspecific reference is made to: Prescott, Ed., Methods in Cell Biology,Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq., thecontents of which is incorporated herein by reference.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the compounds of the present inventionwith for example suitable non-irritating excipients or carriers such ascocoa butter, polyethyleneglycol or a suppository wax, which are solidat ordinary temperatures but liquid at body temperature and therefore,melt while in a suitable body cavity and release the active componenttherein.

Dosage forms for topical administration of a compound of Formula Iinclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Compressed gases may be used to disperse a compound of thisinvention in aerosol form. Inert gases suitable for this purpose arenitrogen, carbon dioxide, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the present invention, or apharmaceutically acceptable salt thereof, and 99% to 1% by weight of asuitable pharmaceutical excipient. In one example, the composition willbe between about 5% and about 75% by weight of a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, with the restbeing one or more suitable pharmaceutical excipients. If formulated as afixed dose, such products employ the compounds of this invention withinthe dosage range described above and the other pharmaceutically activeagent(s) within its approved dosage range. Compounds of the instantinvention may alternatively be used sequentially with knownpharmaceutically acceptable agent(s) when a combination formulation isinappropriate.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active components, e.g., atherapeutically effective amount of a compound of Formula I to achievethe desired purpose. In some embodiments, a pharmaceutical compositioncomprises a quantity of the inventive compound of Formula I formulatedin a unit dose form which may be generally varied or adjusted from about0.01 milligram to about 100 milligrams, preferably from about 0.1 toabout 50 milligrams, more preferably from about 0.5 to about 25milligrams, and typically from about 1 to about 10 milligrams, accordingto the particular application. In some embodiments, a pharmaceuticalcomposition comprises a therapeutically effective amount of a selectiveanti-allergy benzocycloheptathiophene derivative compound of Formula I,or a compound of Formula I, or a compound as recited in Table 1, and apharmaceutically acceptable carrier, vehicle or excipient. In someembodiments, the present invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a selectiveanti-allergy benzocycloheptathiophene derivative compound, wherein theselective anti-allergy benzocycloheptathiophene derivative compound isrecited in Table 1, and the compound is in admixture with apharmaceutically acceptable carrier, vehicle or excipient. Anotherillustrative pharmaceutical composition can include a therapeuticallyeffective amount of a selective anti-allergy benzocycloheptathiophenederivative compound comprising4-[1-(5-methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one,in admixture with a pharmaceutically acceptable carrier, vehicle orexcipient. In one example of a pharmaceutical composition, thepharmaceutical composition comprises a pharmaceutical unit-dosecomposition comprising a selective anti-allergy benzocycloheptathiophenederivative compound of Formula I, the compound is present in thepharmaceutical unit-dose composition in an amount ranging from about0.01 milligram to about 100 milligrams, preferably from about 0.1 toabout 50 milligrams, more preferably from about 0.5 to about 25milligrams, and typically from about 1 to about 10 milligrams, thecompound is in admixture with at least one pharmaceutically acceptablecarrier, vehicle or excipient. Still further examples of pharmaceuticalcompositions include a pharmaceutical unit-dose composition comprising aselective anti-allergy benzocycloheptathiophene derivative compoundprovided in Table 1, the compound is present in the pharmaceuticalunit-dose composition in an amount ranging from about 0.01 milligram toabout 100 milligrams, preferably from about 0.1 to about 50 milligrams,more preferably from about 0.5 to about 25 milligrams, and typicallyfrom about 1 to about 10 milligrams, the compound is in admixture withat least one pharmaceutically acceptable carrier, vehicle or excipient.In some embodiments, the pharmaceutical unit-dose composition comprisesa therapeutically effective amount of4-[1-(5-methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one,the compound is present in the pharmaceutical unit-dose composition inan amount ranging from about 0.01 milligram to about 100 milligrams,preferably from about 0.1 to about 50 milligrams, more preferably fromabout 0.5 to about 25 milligrams, and typically from about 1 to about 10milligrams, the compound is in admixture with at least onepharmaceutically acceptable carrier, vehicle or excipient.

The actual dosage employed may be varied depending upon the patient'sage, sex, weight and severity of the condition being treated. Suchtechniques are well known to those skilled in the art. In oneillustrative embodiment, a unit dose comprises a solid tabletpharmaceutical composition containing 1 mg of Compound A in the freebase form, equivalent to about 1.29 mg Compound A in the hydrogenfumarate salt form. In another illustrative embodiment, 5 mL of a syrupis a unit dose containing 1 mg/5 mL of Compound A in free base formwhich is equivalent to 1.29 mg/5 mL Compound A in the hydrogen fumaratesalt form.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a Compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state in accordance with the teachings of this invention.

Ophthalmic Compositions

Ophthalmic formulations including eye ointments, powders, sprays, liquiddrops, washes, ointments, topical liposome formulations are alsocontemplated as being within the scope of this invention. As usedherein, “concentration” of a component of an ophthalmic compositionmeans concentration based on mass of the component per total volume ofthe composition (i.e., g/mL, or wt/vol), and is typically expressed as apercentage.

In some embodiments, an ophthalmic composition can include aconcentration of a compound of formula I, in a free base form, or anequivalent salt form, for example, a fumarate salt form, ranging fromabout 0.01% to about 0.1%, or from about 0.02% to about 0.05% inadmixture with a suitable ophthalmic carrier. In some embodiments, anophthalmic composition can include a concentration of4-[1-(5-methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneranging from about 0.01% to about 0.1% (wt/vol). In some embodiments,for topical ophthalmic administration, the ophthalmic carrier caninclude: water, mixtures of water and water-miscible solvents, such asC₁- to C₇-alkanols, vegetable oils or mineral oils comprising from 0.5to 5 percent by weight ethyl oleate, hydroxyethylcellulose,carboxymethylcellulose, polyvinylpyrrolidone and other non-toxicwater-soluble polymers for ophthalmic uses, may include, cellulosederivatives, such as methylcellulose, alkali metal salts ofcarboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,methylhydroxypropylcellulose and hydroxypropylcellulose, acrylates ormethacrylates, such as salts of polyacrylic acid or ethyl acrylate,polyacrylamides, natural products, such as gelatin, alginates, pectins,tragacanth, karaya gum, xanthan gum, carrageenan, agar and acacia,starch derivatives, such as starch acetate and hydroxypropyl starch, andalso other synthetic products, such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferablycross-linked polyacrylic acid, such as neutral Carbopol, or mixtures ofthose polymers. Preferred carriers are water, cellulose derivatives,such as methylcellulose, salts of carboxymethylcellulose,hydroxymethylcellulose, hydroxyethylcellulose,methylhydroxypropylcellulose and hydroxypropylcellulose, neutralCarbopol, or mixtures thereof. A highly preferred carrier is water. Theconcentration of the carrier is, for example, from 1 to 100,000 timesthe concentration of the active ingredient.

In some embodiments, the ophthalmic composition for topicaladministration may optionally also include a non-ionic tonicity agent.In some embodiments, a non-ionic tonicity agent includes glycerol,although other non-ionic tonicity agents may be used such as, forexample, urea, sorbitol, mannitol, propylene glycol, and dextrose. Insome embodiments, the non-ionic tonicity agent is provided in aconcentration such that the composition has an osmolality from 400 to750 milliosmoles/kilogram (mOsm/Kg), preferably from 425 to 700 mOsm/Kg,more preferably from 550 to 700 mOsm/Kg, even more preferably from 600to 700 mOsm/Kg, and yet even more preferably from 650 to 700 mOsm/Kg. Insome embodiments, glycerol is used as the non-ionic tonicity agent in aconcentration of from 3% to 10%, preferably from 4% to 8%, morepreferably from 5% to 7%, even more preferably from 5.5. % to 6.5%, andyet even more preferably from 5.75% to 6.25%. In yet other embodiments,glycerol is used as the non-ionic tonicity agent in a concentration ofgreater than 3.5%, preferably greater than 4.5%, more preferably greaterthan 5.5%, even more preferably from 5% to 7%, and yet even morepreferably from 5.5% to 6.5%, such that the composition has anosmolality from 400 to 750 mOsm/Kg, preferably from 425 to 700 mOsm/Kg,more preferably from 550 to 700 mOsm/Kg, even more preferably from 600to 700 mOsm/Kg, and yet even more preferably from 650 to 700 mOsm/Kg.

The ophthalmic compositions of the present invention may optionally alsoinclude one or more preservatives, particularly when the composition ispackaged as a multi-dose application. Illustrative preservatives caninclude: benzalkonium chloride, polyquad preservative (Alcon); perborate(e.g., sodium perborate from Ciba); purite preservative (stabilizedchlorine dioxide) (Allergan); other quaternary ammonium compounds suchas benzoxonium chloride; alkyl-mercury salts of thiosalicylic acid suchas, for example, thiomersal, phenylmercuric nitrate, phenylmercuricacetate, and phenylmercuric borate; parabens such as, for example,methylparaben or propylparaben; alcohols such as, for example,chlorobutanol, benzyl alcohol, and phenyl ethanol; guanidine derivativessuch as, for example, chlorhexidine or polyhexamethylene biguanide; andthe like. When a preservative is used in the ophthalmic composition, thepreservative is typically provided in a concentration of 0.005% to0.02%, preferably 0.01%, although other concentrations may be used.

In one embodiment, a solution to be used as an eyedrop liquid suspensioncomprises about 0.025% of Compound A in free base form which isequivalent to Compound A in hydrogen fumarate salt form at 0.032%.

In one illustrative example, an ophthalmic composition in the form of atopical solution can include: (1) Compound A, 0.25 mg (0.025%); (2)Benzalkonium chloride, 0.10 mg (0.010%); (3) Glycerol 100%, 21.25 mg(2.125%); (4) Sodium hydroxide 1 N, about 0.75 mg (.about. 0.075%); and(5) Water for injection (sterile) to make up 1.0 mL.

Methods of Administering

The compositions of the invention may be in a form suitable foradministration by injection, in the form of a formulation suitable fororal ingestion (such as capsules, tablets, caplets, elixirs, forexample), in the form of an ointment, cream or lotion suitable fortopical administration, in a form suitable for delivery as an eye drop,in an aerosol form suitable for administration by inhalation, such as byintranasal inhalation or oral inhalation, in a form suitable forparenteral administration, that is, subcutaneous, intramuscular,intraperitoneal or intravenous injection. Typically, dosages of thecompound of the invention which may be administered to an animal,preferably a human, will vary depending upon any number of factors,including but not limited to, the type of animal and type of diseasestate being treated, the age of the animal and the route ofadministration.

Pharmaceutical compositions of the invention formulated for pulmonarydelivery may also provide the active ingredient or active ingredients,in the form of droplets of a solution or suspension. Such formulationsmay be prepared, packaged, or sold as aqueous or dilute alcoholicsolutions or suspensions, optionally sterile, comprising the activeingredient, or active ingredients and may conveniently be administeredusing any nebulization or atomization device. Such formulations mayfurther comprise one or more additional non-active ingredients forexample, a flavoring agent such as saccharin sodium, a volatile oil, abuffering agent, a surface active agent, or a preservative such asmethylhydroxybenzoate. The droplets provided by this route ofadministration preferably have an average diameter in the range fromabout 0.1 to about 200 nanometers. The formulations described herein asbeing useful for pulmonary delivery are also useful for intranasaldelivery of a pharmaceutical composition of the invention.

In some embodiments, an exemplary formulation suitable for intranasaladministration is a coarse powder comprising the active ingredient andhaving an average particle size or diameter from about 0.2 to 500micrometers. Such a formulation can be administered by rapid inhalationthrough the nasal passage from a container of the powder held close tothe nares. Formulations suitable for nasal administration may, forexample, comprise from about as little as 0.1% (w/w) and as much as 100%(w/w) of the active ingredient, and may further comprise one or more ofthe additional ingredients described herein.

A pharmaceutical composition of the invention may be prepared, packaged,or sold in a formulation suitable for buccal administration. Suchformulations may, for example, be in the form of tablets or lozengesmade using conventional methods, and may, for example, 0.1 to 50% (w/w)active ingredient, (and ranges inherent therein) the balance comprisingan orally dissolvable or degradable composition and, optionally, one ormore of the additional non-active ingredients described herein.Alternately, formulations suitable for buccal administration maycomprise a powder or an aerosolized or atomized solution or suspensioncomprising the active ingredient or active ingredients. Such powdered,aerosolized, or aerosolized formulations, when dispersed, preferablyhave an average particle or droplet size in the range from about 0.1 toabout 200 nanometers, and may further comprise one or more of theadditional non-active ingredients described herein.

As used herein, “additional non-active ingredients” include, but are notlimited to, one or more of the following: excipients; surface activeagents; dispersing agents; inert diluents; granulating anddisintegrating agents; binding agents; lubricating agents; sweeteningagents; flavoring agents; coloring agents; preservatives;physiologically degradable compositions such as gelatin; aqueousvehicles and solvents; oily vehicles and solvents; suspending agents;dispersing or wetting agents; emulsifying agents, demulcents; buffers;salts; thickening agents; fillers; emulsifying agents; antioxidants;antibiotics; antifungal agents; stabilizing agents; and pharmaceuticallyacceptable polymeric or hydrophobic materials. Other “additionalnon-active ingredients” which may be included in the pharmaceuticalcompositions of the invention are known in the art and described, forexample in Genaro, ed. (1985, Remington's Pharmaceutical Sciences, MackPublishing Co., Easton, Pa.), which is incorporated herein by reference.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount which willvary depending upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof the compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular disease-states, and the host undergoingtherapy. Generally, the human oral dosage form containing the activeingredients can be administered 1 or 2 times per day. The amount andfrequency of the administration will be regulated according to thejudgment of the attending clinician. The compounds of the presentinvention can be administered to a patient at dosage levels in the rangeof about 0.01 to about 100 mg per day in single or divided doses. For anormal human adult having a body weight of about 70 kilograms, a dosagein the range of about 0.0001 to about 10 mg per kilogram of body weightper day, or more preferably from about 0.0005 to about 1 mg per kilogramof body weight per day, or from about 0.001 to about 0.5 mg per kilogramof body weight is an example. The specific dosage used, however, canvary. For example, the dosage can depend on a number of factorsincluding the requirements of the patient, the severity of the conditionbeing treated, and the pharmacological activity of the compound beingused. The determination of optimum dosages for a particular patient iswell known to one of ordinary skill in the art.

For ophthalmic compositions, typically, the compositions areadministered as drops, with one drop of the composition being applied toan eye of the subject suffering from or susceptible to allergicconjunctivitis two times per day, although more or less of thecomposition may be used in more or less frequent doses depending onmultiple factors, including the makeup of the particular composition.

Typically, in therapeutic applications, the treatment would be for theduration of the disease state or condition. Further, it will be apparentto one of ordinary skill in the art that the optimal quantity andspacing of individual dosages will be determined by the nature andextent of the disease state or condition being treated, the form, routeand site of administration, and the nature of the particular individualbeing treated. Also, such optimum conditions can be determined byconventional techniques.

It will also be apparent to one of ordinary skill in the art that theoptimal course of treatment, such as, the number of doses of thecomposition given per day for a defined number of days, can beascertained by those skilled in the art using conventional course oftreatment determination tests. The administration of the pharmaceuticalcompositions above can be repeated several times, preferably at leastone to five times, in daily, weekly, or monthly intervals. In someembodiments, a unit dose may be administered one to three times per dayor once per day in sustained release form, to relieve one or moresymptoms of allergy or allergic diseases described herein. The frequencyof dosing can be experimentally verified in clinical trials and arerecommended to provide a reasonable benefit/risk ratio commensurate withthe experience of the prescribing clinician. Methods for determining thetherapeutic effectiveness of the compositions described herein for thetreatment of various allergic diseases or conditions are well within theskill of the ordinary artisan. For example, symptoms of atopicdermatitis can, for example be scored as described in N. Engl. J. Med1997, 337:816-21. Symptoms of asthma can be scored by various methodsincluding questionnaires described in Juniper et al., Health Qual. LifeOutcomes, 2005 Sep. 16, 3:58, and combinations of questionnaires andspirometric measurements, for example, the severity of asthma symptomscan be assessed by spirometric measurements of pulmonary functionsbefore and after administration of methacholine as described in N. Engl.J. Med 2000, 343:1054-63. These references are incorporated herein byreference. Pollen allergy can, inter alia, be assessed using a nasalprovocation test, other allergies, e.g. food allergens, chemicalallergens, plant allergens, house dust or dust mite allergens, can beassessed using a conjunctival provocation procedure or a skin prick testroutinely used in immunology or allergy clinics.

Methods of Treating Allergic Diseases and Disorders

In some embodiments, the present invention provides methods for treatingan allergic disease or symptoms associated therewith in a subject inneed thereof, the method comprising administering a therapeuticallyeffective amount of an anti-allergy benzocycloheptathiophene derivativecompound of Formula I or a pharmaceutically acceptable salt thereof,solvate, or prodrug thereof, and a pharmaceutically acceptable carrier,vehicle or excipient. In some embodiments, the compound of Formula I isin the form of a fumarate salt. In some embodiments, the fumarate saltof the compound of Formula I is a fumarate salt of a compound ofTable 1. In some embodiments, the fumarate salt of the compound ofFormula I is a fumarate salt of4-[1-(5-methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one.In some embodiments, the compound of Formula I can be in admixture withone or more pharmaceutically acceptable excipients (non-activeingredients) as described above. Optionally, the pharmaceuticalcomposition may contain one or more additional therapeutic agents asdescribed below for the treatment of an allergy, allergic disease,hypersensitive associated disease or respiratory disease associated withairway inflammation, such as asthma. In some embodiments, thecompositions of the present invention are effective in preventing,treating or alleviating one or more symptoms related to anaphylaxis,drug hypersensitivity, skin allergy, eczema, allergic rhinitis,urticaria, atopic dermatitis, dry eye disease, allergic contact allergy,food hypersensitivity, allergic conjunctivitis, insect venom allergy,bronchial asthma, allergic asthma, intrinsic asthma, occupationalasthma, atopic asthma, acute respiratory distress syndrome (ARDS) andchronic obstructive pulmonary disease (COPD).

Hypersensitivity associated diseases or disorders that may be treated bythe methods of the invention include, but are not limited to,anaphylaxis, drug reactions, skin allergy, eczema, allergic rhinitis,urticaria, atopic dermatitis, dry eye disease (or otherwise referred toas Keratoconjunctivitis sicca (KCS), also called keratitis sicca,xerophthalmia), allergic contact allergy, food allergy, allergicconjunctivitis, insect venom allergy and respiratory diseases associatedwith airway inflammation, for example, IgE mediated asthma and non-IgEmediated asthma.

The respiratory diseases associated with airway inflammation mayinclude, but are not limited to, rhinitis, allergic rhinitis, bronchialasthma, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma,occupational asthma, atopic asthma, exercise induced asthma,cough-induced asthma, acute respiratory distress syndrome (ARDS) andchronic obstructive pulmonary disease (COPD). In some embodiments, thepresent invention provides methods for treating or alleviating thesymptoms of an allergic disease, the method comprises administering atherapeutically effective amount of an anti-allergybenzocycloheptathiophene derivative compound of Formula I or apharmaceutically acceptable salt thereof, solvate, or prodrug thereof,and a pharmaceutically acceptable carrier, vehicle or excipient to thesubject. In some embodiments, the present invention provides a methodfor treating asthma in a subject in need thereof, the method comprisesadministering a therapeutically effective amount of an anti-allergybenzocycloheptathiophene derivative compound of Formula I or apharmaceutically acceptable salt thereof, solvate, or prodrug thereof.In some embodiments, the compound of Formula I, can be present in acomposition in a free base form, or an equivalent salt form, forexample, a fumarate salt form, in a unit dose or a daily dose rangingfrom about 0.0001 to about 10 mg per kilogram of body weight, or fromabout 0.0005 to about 1 mg per kilogram of body weight. In someembodiments, the compound of Formula I can be present in a compositionin a free base form, or an equivalent salt form, in admixture with asuitable pharmaceutical carrier, vehicle or excipient. In someembodiments, a method for treating asthma in a subject in need thereofcomprises administering a composition containing4-[1-(5-methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneor a pharmaceutically acceptable salt thereof, or solvate or prodrugthereof, the4-[1-(5-methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneis administered in a unit dose or a daily dose ranging from about 0.0001to about 10 mg per kilogram of body weight, or from about 0.0005 toabout 1 mg per kilogram of body weight. In some embodiments, a methodfor treating asthma comprises administering a therapeutically effectiveamount of an anti-allergy benzocycloheptathiophene derivative compoundof Formula I or Table 1, or a pharmaceutically acceptable salt thereof,solvate, or prodrug thereof, wherein the compound or pharmaceuticallyacceptable salt thereof, solvate, or prodrug thereof is administered tothe subject in an amount from 0.0001 to about 10 mg per kilogram of bodyweight per day.

In one embodiment, the invention provides compositions comprising acompound of Formula I and methods for treating pulmonary diseases by wayof oral or inhalation administration of the compositions of theinvention. Preferably, the composition prevents hyper-responsiveness inairway and reduces the hypersensitivity of the airway due to mast cellinvolvement (for example, IgE mediated mast cell degranulation) andcytokine overproduction by immune effector cells such as mast cells,basophils, eosinophils, neutrophils, monocytes, macrophages, dendriticcells and T-cells. In one aspect, the compositions of the inventionprevent bronchoconstriction in response to histamine and cholinergicchallenges. In another aspect, the compositions diminish IL-13-inducedhyper responsiveness to cholinergics. In yet another aspect, thecompositions block bronchoconstriction secondary to IgE-mediated mastcell degranulation and improper cytokine immune responses.

In some embodiments, the compound of Formula I and/or an additionaltherapeutic agent described in detail below can be administered intherapeutically effective doses, or alternatively in subclinicaleffective doses. When the anti-allergy benzocycloheptathiophenederivative compound of Formula I is used in combination with anadditional therapeutic agent to treat or prevent allergy, an allergicdisease or symptoms related thereto in a human patient, the presentlydisclosed anti-allergy benzocycloheptathiophene derivative compounds ofFormula I and additional therapeutic agents can be present in apharmaceutically or anti-allergy or anti-inflammatory effective amount.By virtue of their additive or synergistic effects, when used in thecombinations described above, each can also be present in a subclinicalpharmaceutically effective or anti-allergy or anti-inflammatoryeffective amount, i.e., an amount that, if used alone, provides reducedpharmaceutical effectiveness in completely inhibiting or reducing theproduction of cytokines or mast cell degranulation and/or reducing orameliorating conditions or symptoms associated with allergic reaction,inflammation and cytokine overexpression in patients compared to suchanti-allergy benzocycloheptathiophene derivative compounds of Formula Iand additional therapeutic agents when used in pharmaceuticallyeffective amounts.

While the methods of the present invention can be used to treat orameliorate the symptoms associated with allergy, allergic disease orairway inflammation, the compounds of the invention can also be used toinhibit or ameliorate one or more inappropriate immune responses ortheir symptoms in allergy, asthma, autoimmunity, inflammation, orrelated conditions. The effects of the compounds include detectablyameliorating one or more of (1) the activation and degranulation of mastcells, (2) reducing unwanted cytotoxic immune cell hypersensitivity, (3)reducing unwanted autoantibody or other antibody synthesis, e.g., anunwanted IgA, IgE, IgG or IgM, in allergy, asthma or another autoimmuneor inflammation condition, (4) inhibiting the development, proliferationor unwanted activity of autoreactive T or B cells, (5) altering theexpression of one or more cytokines, interleukins or cell surfaceantigens, e.g., a cytokine, interleukin or cell surface antigendescribed herein, (6) decreasing eosinophilia in allergy conditions, (7)detectably decreasing the level or activity of one or more of ICAM-1,IL-1.alpha., IL-1.beta., TNF.alpha., IL-13, IL-4, IL-6 or IL-8 in, e.g.,inflammation conditions or in autoimmune conditions, (8) decreasing thelevel or biological activity of one or more of TNF, IFN-.gamma., andIL-1, (9) reducing induction of arachidonic acid metabolism or reducingeicosanoid metabolites such as thromboxanes or prostaglandins in, e.g.,asthma, (10) reducing IL-4, IL-6, IL-8 or IL-10 synthesis, levels oractivity in, e.g., allergy or inflammation such as idiopathic pulmonaryfibrosis or allergic asthma or (11) reducing or interfering withneutrophil chemotaxis by, e.g., reducing thioredoxin release fromaffected cells in conditions such as infections, inflammation orautoimmunity.

In one embodiment, the invention is a method of the prophylaxis ortreatment of asthma comprising administering a composition of theinvention to a subject in need of such treatment, wherein the amount ofthe composition is sufficient for the prophylaxis or treatment of asthmain the subject. In asthma, chronic inflammatory processes in the airwayplay a central role in increasing the resistance to airflow within thelungs. Many cells and cellular elements are involved in the inflammatoryprocess, particularly mast cells, eosinophils, basophils, T-lymphocytes,neutrophils, epithelial cells. The reactions of these cells result in anassociated increase in the existing sensitivity and hyper-responsivenessof the airway smooth muscle cells that line the airways to theparticular stimuli involved. Therefore, the invention also includesrapidly treating asthma with a compound of the invention, wherein thecompound is able to regulate the production of pro-inflammatorymediators from various immune cells. Rapidly treating asthma can meanthat the administration of a therapeutically effective dosage of acomposition of the invention will result in an observable reduction inat least one symptom of the asthmatic condition in a subject, within 4hours, or within 3 hours, or within 2 hours, or within 1 hour, or within30 minutes of administration. In some embodiments, the compounds of thepresent invention when administered to a subject with asthma andexperiencing symptoms of asthma may also provide symptomatic relief ofthe subject's asthma for periods of time ranging from about 1 hour toabout 72 hours, or from about 1 hour to about 48 hours, or from about 1hour to about 24 hours or from about 1 hour to about 12 hours or fromabout 1 hour to about 4 hours, or from about 2 hours to about 72 hours,or from about 6 hours to about 72 hours, or from about 12 hours to about72 hours, or from about 18 hours to about 72 hours, or from about 24hours to about 72 hours, or from about 48 hours to about 72 hours, orfrom about 60 hours to about 72 hours after the initial administrationof a pharmaceutically effective amount of a composition comprising acompound of Formula I.

Reducing inflammation and edema of the tissue surrounding the airway canalso increase the diameter of an airway. Inflammation and edema(accumulation of fluid) of the airway are chronic features of asthma.The inflammation and edema can be reduced by application of a compoundof the invention to stimulate wound healing and regenerate normaltissue. Healing of the epithelium or sections of the epitheliumexperiencing ongoing denudation and renewal allows regeneration ofhealthy epithelium with less associated airway inflammation. The lessinflamed airway has an increased airway diameter both at a resting stateand in constriction. Inflammatory mediators released by tissue in theairway wall may serve as a stimulus for airway smooth musclecontraction. Therapy that reduces the production and release ofinflammatory mediators can reduce smooth muscle contraction,inflammation of the airways, and edema. Examples of inflammatorymediators are cytokines, chemokines, and histamine. The tissues whichproduce and release inflammatory mediators include, but are not limitedto: airway smooth muscle, epithelium, mast cells, eosinophils andbasophils. Treatment of these structures with a compound of theinvention can reduce the ability of the airway structures to produce orrelease pro-inflammatory mediators. The reduction in releasedinflammatory mediators can reduce chronic inflammation, therebyincreasing the airway inner diameter, and may also reducehyper-responsiveness of the airway smooth muscle.

Without wishing to be bound by any particular theory, it is believedthat the compounds of the invention can be used to treat asthma. This isbecause the compounds of the invention are capable of at leastmodulating the immune response. Preferably, the method of treatingasthma encompasses administering a compound of Table 1 or apharmaceutically acceptable salt thereof, solvate, or prodrug thereofpresent in a pharmaceutically acceptable composition, the compound orpharmaceutically acceptable salt thereof, solvate, or prodrug thereof isadministered to the subject in an amount from 0.0001 to about 10 mg perkilogram of body weight per day.

Results presented herein demonstrate that the compounds of the inventionexhibit a desirable oral bioavailability at a low dose. For example, itwas observed that oral administration of a compound of the presentinvention orally caused a significant block in DNP-induced swelling andincrease the weight of the ear and the feet in an animal model,comparable to a known allergy treatment compound, ketotifen and in someassays even surpassing the activity of ketotifen (See foot weight ofCompound treated mice in FIG. 3B). These results suggest that thecompounds of the present invention as illustrated in Example 7 below,have therapeutic effects on allergic inflammation after allergenchallenge in vivo. Thus, invention provides a method of achieving thedesired bioavailability of the active ingredient.

In one embodiment, the invention is a method of the prophylaxis ortreatment of COPD comprising administering a composition of theinvention to a subject in need of such treatment, wherein the amount ofthe composition is sufficient for the prophylaxis or treatment of COPDin the subject.

In one embodiment, the invention is a method of the prophylaxis ortreatment of bronchoconstriction, lung inflammation or lung allergycomprising administering a composition of the invention to a subject inneed of such treatment, wherein the amount of the composition issufficient for the prophylaxis or treatment of bronchoconstriction, lunginflammation or lung allergy in the subject.

The allergic reaction in humans and animals has been extensively studiedand the basic immune mechanisms involved are well known. Allergicconditions or diseases in humans include but are not limited to eczema,allergic rhinitis or coryza, hay fever, conjunctivitis, bronchial orallergic asthma, urticaria (hives) and food allergies; atopicdermatitis; anaphylaxis; drug allergy; angioedema; and allergicconjunctivitis. Allergic diseases in dogs include but are not limited toseasonal dermatitis; perennial dermatitis; rhinitis: conjunctivitis;allergic asthma; and drug reactions. Allergic diseases in cats includebut are not limited to dermatitis and respiratory disorders; and foodallergens. Allergic diseases in horses include but are not limited torespiratory disorders such as “heaves” and dermatitis. Allergic diseasesin non-human primates include but are not limited to allergic asthma andallergic dermatitis.

The generic name for molecules that cause an allergic reaction isallergen. There are numerous species of allergens. The allergic reactionoccurs when tissue-sensitizing immunoglobulin of the IgE type reactswith foreign allergen. The IgE antibody is bound to mast cells and/orbasophils, and these specialized cells release chemical mediators(vasoactive amines) of the allergic reaction when stimulated to do so byallergens bridging the ends of the antibody molecule. Histamine,platelet activating factor, arachidonic acid metabolites, and serotoninare among the best known mediators of allergic reactions in humans.Histamine and the other vasoactive amines are normally stored in mastcells and basophil leukocytes. The mast cells are dispersed throughoutanimal tissue and the basophils circulate within the vascular system.These cells manufacture and store histamine within the cell unless thespecialized sequence of events involving IgE binding occurs to triggerits release.

Accordingly, the compounds of the invention can be used to reduceIgE-mediated mast cell degranulation and related responses at least inpart, by decreased production of one or more biological mediators, e.g.,substance P neuropeptide, thymus- and activation-regulated chemokine,lipid mediators and cytokines, for example, TNF-α, MCP-1, RANTES,CXCL10, CXCL8 (IL-8), IL-1, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13,and IL-23, by one or more other cell types such as eosinophils and otherimmune cells as described herein.

In one illustrative example, the compounds of the invention can be usedto reduce the symptoms, inhibit the asthmatic reaction, or prevent anallergic response. In some embodiments, the compounds of the inventionare useful for treating and/or ameliorating the symptoms of both asthmaand allergy. In some embodiments, the prophylactic or treatment methodscontemplated herein include the use of the compounds of the invention incombination optionally with other suitable therapies or additionaltherapeutic agents (e.g., asthma/allergy medicament). An additionaltherapeutic agent as used herein is a composition of matter that reducesthe symptoms, inhibits the asthmatic or allergic reaction, or preventsthe development of an allergic or asthmatic reaction. In still furtherembodiments of the method for treating or alleviating the symptoms of anallergic disease or respiratory disease (e.g. asthma), the method alsoincludes administering an anti-allergy benzocycloheptathiophenederivative compound of Formula I or a pharmaceutically acceptable saltthereof, solvate, or prodrug thereof, optionally in combination with anadditional therapeutic agent, for example, an anti-inflammatory agent,an antibiotic, a bronchodilator/beta-2 agonist, an adrenergic agonist, amethylxanthine compound, an antihistamine, a prostaglandin inducer, aninhaled glucocorticoid, a systemic glucocorticoid, an immunomodulator, aleukotriene modifier, an IgE blocker, a mast cell stabilizer, ananticholinergic, methotrexate, a PDE-₄ inhibitor, a K⁺ channel opener, aVLA-4 antagonist, a neurokin antagonist, a TXA2 synthesis inhibitor, axanthanine compound, an arachidonic acid antagonist, a 5-lipoxygenaseinhibitor, a thromboxin A2 receptor antagonist, a thromboxane A2antagonist, an inhibitor of 5-lipoxygenase activation protein, aprotease inhibitor and combinations thereof.

Use of such combination provides an improved sustained pharmacologiceffect that translates to an improved disease management. For instance,the efficacy of the combination of the compounds of the invention withan additional therapeutic agent is improved over the use of each of themedicaments alone. In some instances, the combination of a compound ofthe invention with an additional therapeutic agent works in asynergistic manner. In some instances, the combination of a compound ofthe invention with an additional therapeutic agent works in an additivemanner. In some instances, the combination of a compound of theinvention with an additional therapeutic agent works to reduce theseverity of a side effect inherent in the use of either agent when usedalone.

In some embodiments, an additional therapeutic agent comprises abronchodilator and/or β₂ adrenoceptor agonist. Bronchodilator or β₂adrenoceptor agonists are a class of compounds that causesbronchodilation or smooth muscle relaxation. Bronchodilator and/orβ₂adrenoceptor agonists include, but are not limited to, salmeterol(Serevent™, GlaxoSmithKline), salbutamol, also known as albuterol;Ventolin™/Ventorlin™, GlaxoSmithKline; Asthalin™, Cipla; Proventil™,Schering-Plough; Pro-Air™, Teva), terbutaline(Brethine™/Bricanyl™/Brethaire™), formoterol (Foradil™/Foradile™,Novartis; Oxis™, Astra Zeneca; Atock™, Astellas; Perforomist™, Dey),fenoterol (Berotec™, Boehringer-Ingelheim), bitolterol (Tornalate™, ElanPharmaceuticals), pirbuterol (Maxair™, 3M), and orciprenaline(Alotec™/Alupent™/Metaprel™/Novasmasol™).

Long-acting β₂adrenoceptor agonists and bronchodilators are used forlong-term prevention of symptoms in addition to the anti-inflammatorytherapies. They cause bronchodilation or smooth muscle relaxation, byactivating adenylate cyclase, increasing cyclic AMP and producingfunctional antagonism of bronchoconstriction. These compounds alsoinhibit mast cell mediator release, decrease vascular permeability andincrease mucociliary clearance. Long-acting β₂ adrenoceptor agonistsinclude, but are not limited to, salmeterol, also known as albuterol.These compounds are usually used in combination with corticosteroids andgenerally are not used without any inflammatory therapy. They have beenassociated with side effects such as tachycardia, skeletal muscletremor, hypokalemia, and the like. The most common combinations ofinhaled steroids and long-acting bronchodilators currently in use arefluticasone/salmeterol (Advair™/Seretide™, GlaxoSmithKline), andbudenoside/formoterol (Symbicort™, AstraZeneca).

Short-acting β₂ adrenoceptor agonists/bronchodilators relax airwaysmooth muscle, causing the increase in airflow. These classes ofcompounds are preferred drugs for the treatment of acute asthmaticsystems. Short-acting β₂ adrenorecptor agonists include, but are notlimited to, bitolterol (Tornalate™, Elan Pharmaceuticals), pirbuterol(Maxair™, 3M), and terbutaline (Brethine™/Bricanyl™/Brethaire™). Some ofthe adverse effects associated with the use of short-acting β₂adrenorecptor agonists include tachycardia, skeletal muscle tremor,hypokalemia, increased lactic acid, headache, and hyperglycemia. Olderand less selective adrenergic agonists, such as inhaled epinephrine andephedrine tablets, have also been used in the treatment of asthma. Theseagents cause similar or lesser rates of cardiac side effects asalbuterol. Inhaled epinephrine may be used to terminate an acuteasthmatic exacerbation. These agents may be given parenterally, butadverse effects may arise from this route of administration.

In some embodiments, the additional therapeutic agent can comprise amethylxanthine compound including for instance theophylline (also knownas dimethylxanthine;

Elixophillin™/Theolair™/Theocin™/Nuelin™/Synophylate™/Bronkodyl™/Aerolate™/Theovent™),doxofylline (Maxivent™/Ansimar™/Ventax™), and aminophylline(Phyllocontin™/Truphylline™/Minomal™), have been used for long-termcontrol and prevention of symptoms. These compounds causebronchodilation resulting from phosphodiesterase inhibition and likelyadenosine antagonism. It is also believed that these compounds mayeffect eosinophilic infiltration into bronchial mucosa and decreaseT-lymphocyte numbers in the epithelium. Dose-related acute toxicitiesare a particular problem with these compounds. As a result, routineserum concentration must be monitored in order to account for thetoxicity and narrow therapeutic range arising from individualdifferences in metabolic clearance. Side effects include tachycardia,nausea and vomiting, tachyarrhythmias, central nervous systemstimulation, headache, seizures, hematemesis, hyperglycemia andhypokalemia.

Other asthma/allergy additional therapeutic agents can be used incombination with the compounds of the invention to treat allergy.Additional therapeutic agents useful in the treatment of allergyinclude, but are not limited to, anti-histamines, prostaglandininducers, and steroids.

In some embodiments the additional therapeutic agent is ananti-histamine agent. Anti-histamines counteract histamine released bymast cells or basophils. These compounds are well known in the art andcommonly used for the treatment of allergy. Anti-histamines include, butare not limited to, loratidine (Claritin™/Claritin-D™, Schering-Plough;Alayert™, Wyeth), cetirizine (Zyrtec™/Reactine™, Pfizer) and analogues,buclizine Vibazine™/Histabutizine™/Buclifen™/Buclodin™/Longifene),fexofenadine (Allegra™/Telfast™, Sanofi-Aventis), terfenadine (Seldane™,Schering-Plough), desloratadine(NeoClarityn™/Claramax™/Clarinex™/Aerius™, Schering-Plough),norastemizole (Soltara™, Sepracor), epinastine (Elestat™/Relestat™,Allergan), ebastine (Kestine™/Evastin™/Ebastel™/Aleva™, Pharmacare),astemizole (Hismanal™, Janssen), levocabastine (Livostin™, Janssen),azelastine (Astelin™, Meda), tranilast (Rizaben™), mizolastine(Mizollen™), betahistine (SERC™), and the like.

In some embodiments, the additional therapeutic agent can comprise aprostaglandin. Prostaglandin inducers are compounds that induceprostaglandin activity, regulating smooth muscle relaxation. An exampleof a prostaglandin inducer is rebamipide.

The additional therapeutic agents useful in combination with thecompounds of the invention also include steroids and immunomodulators.Glucocorticoids are a class of steroid hormones characterised by anability to bind with the glucocorticoid receptor (GR) and triggersimilar effects. Glucocorticoids are distinguished frommineralocorticoids and sex steroids by their specific receptors, targetcells, and effects. In technical terms, corticosteroid refers to bothglucocorticoids and mineralocorticoids (as both are mimics of hormonesproduced by the adrenal cortex), but is often used as a synonym forglucocorticoid. In this document, glucocorticoid and corticosteroid areused interchangeably.

In some embodiments, the additional therapeutic agent can comprise acorticosteroid. Corticosteroids are used long-term to preventdevelopment of the symptoms, and suppress, control, and reverseinflammation arising from an initiator. Some corticosteroids can beadministered by inhalation and others are administered systemically. Thecorticosteroids that are inhaled have an anti-inflammatory function byblocking late-reaction allergen and reducing airwayhyper-responsiveness. These drugs also inhibit cytokine production,adhesion protein activation, and inflammatory cell migration andactivation. They are also believed to reverse β₂-receptor downregulationand to inhibit microvascular leakage.

Corticosteroids are used generally for moderate to severe exacerbationsto prevent the progression, reverse inflammation and speed recovery fromthe disease. Cortosteroids are associated with reversible abnormalitiesin glucose metabolism, increased appetite, fluid retention, weight gain,mood alteration, hypertension, peptic ulcer, and rarely ascepticnecrosis of femur. These compounds are useful for short-term (e.g., 3-10days) prevention of the inflammatory reaction in inadequately controlledpersistent asthma. They also function in a long-term prevention ofsymptoms in severe persistent asthma to suppress and control andactually reverse inflammation. The side effects associated with systemiccorticosteroids are even greater than those associated with inhaledcorticosteroids. Some side effects associated with longer term useinclude adrenal axis suppression, growth suppression, dermal thinning,hypertension, diabetes, Cushing's syndrome, cataracts, muscle weakness,and in rare instances, impaired immune function.

The combination of the compounds of the invention and steroids areparticularly well suited to the treatment of young subjects (e.g.,children). To date, the use of steroids in children has been limited bythe observation that some steroid treatments have been reportedlyassociated with growth retardation. Thus, according to the presentinvention, the compounds of the invention can be used in combinationwith steroids, allowing for the use of lower required doses of steroids.

Corticosteroids include, but are not limited to, beclomethasonedipropionate (inhaler: Becotive™/Qvar™; nasal spray:Beconase™/Vancenase™), budesonide (Rhinocort™/Pulmicort™, AstraZeneca),flunisolide (AeroBid™/Nasaline™/Nasarel™), fluticasone propionate(Flovent™/Flonase™, GlaxoSmithKline; Flixotide™/Flixonase™, Allen &Hanburys), fluticasone furoate (Veramyst™, GlaxoSmithKline) andtriamcinolone(Kenalog™/Aristocort™/Nasacort™/Tri-Nasal™/Triderm™/Azmaco-rt™/Trill™/VolonA™/Tristoject™/Fougera™/Tricortl™/Triesence™). Although dexamethasone isa corticosteroid having anti-inflammatory action, it is not regularlyused for the treatment of asthma/allergy in an inhaled form because itis highly absorbed, it has long-term suppressive side effects at aneffective dose. Dexamethasone, can be used according to the inventionfor the treating of asthma/allergy because, when administered incombination with the compounds of the invention, it can be administeredat a low dose thereby reducing the side effects. Additionally, thecompounds of the invention can be administered to reduce the sideeffects of dexamethasone even at higher concentrations. Some of the sideeffects associated with corticosteroid include cough, dysphonia, oralthrush (candidiasis), and in higher doses, systemic effects, such asadrenal suppression, osteoporosis, growth suppression, skin thinning andeasy bruising.

Systemic corticosteroids include, but are not limited to,methylprednisolone (Medrol™/Solu-Medrol™, Sandoz), prednisolone (Teva,KV Pharmaceutical) and prednisone (Deltasoneprednisone™, Pharmacia &UpJohn).

Inhaled glucocorticoids are the most widely used prevention medicationsand normally come as inhaler devices: ciclesonide (Alvesco™, Nycomed),beclomethasone (inhaler: Becotive™/Qvar™; nasal spray:Beconase™/Vancenase™), budesonide (Rhinocort™/Pulmicort™, AstraZeneca),flunisolide (AeroBid™/Nasaline™/Nasarel™), fluticasone(Flovent™/Flonase™/Veramyst™, GlaxoSmithKline; Flixotide™/Flixonase™,Allen & Hanburys), mometasone (Naslx™/Asmanex Twisthaler™,Schering-Plough), and triamcinolone(Kenalog™/Aristocort™/Nasacort™/Tri-Nasal™/Triderm™/Azmaco-rt™/Trill™/VolonA™/Tristoject™/Fougera™/Tricortl™/Triesence™). Due to the deleteriousside effects of use of corticosteroids, inhaled steroids are generallyused for prevention, as their smaller doses are targeted to the lungs,unlike the higher doses of oral preparations.

In some embodiments, the additional therapeutic agent can comprise animmunomodulator. Immunomodulators include, but are not limited to,anti-inflammatory agents, leukotriene antagonists, IL-4 muteins, solubleIL-4 receptors, immunosuppressants, anti-IL-4 antibodies, IL-4antagonists, anti-IL-5 antibodies, soluble IL-13 receptor-Fc fusionproteins, anti-IL-9 antibodies, CCR3 antagonists, CCR5 antagonists,VLA-4 inhibitors, downregulators of IgE, and the like.

In some embodiments, the additional therapeutic agent can comprise aleukotriene modifier. Leukotriene modifiers are often used for long-termcontrol and prevention of symptoms in mild persistent asthma.Leukotrienes are biochemical mediators that are released from mastcells, eosinophils, and basophils that cause contraction of airwaysmooth muscle and increase vascular permeability, mucous secretions andactivate inflammatory cells in the airways of patients with asthma.Leukotriene modifiers function as leukotriene receptor antagonists byselectively competing for LTD-4 and LTE-4 receptors. These compoundsinclude, but are not limited to, montelukast (Singulair™, Merck),zafirlukast (Accolate™/Accoleit™/Vanticon™, AstraZeneca), pranlukast andzileuton (Zyflo™, Abbott). Zileuton tablets function as 5-lipoxygenaseinhibitors.

In some embodiments, the additional therapeutic agent can comprise adown-regulator of IgE. Down-regulators of IgE include peptides or othermolecules with the ability to bind to the IgE receptor and therebyprevent binding of antigen-specific IgE. Another type of down-regulatorof IgE is a monoclonal antibody directed against the IgEreceptor-binding region of the human IgE molecule. Thus, one type ofdown-regulator of IgE is an anti-IgE antibody or antibody fragment. Oneof skill in the art can prepare functionally active antibody fragmentsof binding peptides with the same function. Other types of IgEdown-regulators are polypeptides capable of blocking the binding of theIgE antibody to the Fc receptors on the cell surfaces and displacing IgEfrom binding sites upon which IgE is already bound. An example of an IgEblocker is omalizumab (Xolair™), a recombinant DNA-derived IgGlkmonoclonal antibody that binds selectively to IgE and is made byGenentech/Novartis.

In some embodiments, the additional therapeutic agent can comprise amast cell stablizier. Mast cell stabilizers, as the name implies,stabilize mast cell membranes and inhibit activation and release ofmediators from eosinophils and epithelial cells. Such compounds,exemplified by cromolyn sodium (cromoglicic acid; nasal spray: Rynacrom™(UK), Nasalcrom™, Prevalin™ (Netherlands); inhaler: Intal™; oral form:Gastrocrom™) and nedocromil (inhaler: Tilade™; eye drop: Alocril™), areused as long-term control medications for preventing primarily asthmasymptoms arising from exercise or allergic symptoms arising fromallergens. These compounds are believed to block early and latereactions to allergens by interfering with chloride channel function.

In some embodiments, the additional therapeutic agent can comprise ananticholinergic agent. An anticholinergic agent is a substance thatblocks the neurotransmitter acetylcholine in the central and theperipheral nervous system. Frequently, they reduce the effects mediatedby acetylcholine on acetylcholine receptors in neurons throughcompetitive inhibition. Therefore, their effects are reversible.Anticholinergics are classified according to the receptors that areaffected: (a) antimuscarinic agents operate on the muscarinicacetylcholine receptors; the majority of anticholinergic drugs areantimuscarinics; and (b) antinicotinic agents operate on the nicotinicacetylcholine receptors. Anticholinergics are generally used for therelief of acute bronchospasm. These compounds are believed to functionby competitive inhibition of muscarinic cholinergic receptors.Anticholinergics include, but are not limited to, ipratrapoium bromide(Atrovent™/Apovent™, Boehringer Ingelheim), oxitropium and tiotropium(Spiriva™, Boehringer-Ingelheim/Pfizer). These compounds reverse onlycholinerigically-mediated bronchospasm and do not modify any reaction toantigen. Side effects include drying of the mouth and respiratorysecretions, increased wheezing in some individuals, blurred vision ifsprayed in the eyes. Ipratropium is also combined with albuterol (tradenames Combivent™ and DuIb™) for the management of chronic obstructivepulmonary disease (COPD) and asthma, and with fenoterol (trade namesDuovent™ and Berodual N™) for the management of asthma.

In some embodiments, the additional therapeutic agent can comprisemethotrexate. Methotrexate is an antimetabolite and antifolate drug usedin treatment of cancer and autoimmune diseases. It acts by inhibitingthe metabolism of folic acid. It has come into use as a treatment forsome autoimmune diseases, including ankylosing spondylitis, Crohn'sdisease, psoriasis, psoriatic arthritis, rheumatoid arthritis, andscleroderma, along with difficult-to-treat asthma cases.

In some embodiments, useful additional therapeutic agents which can becombined with a compound of Formula I can include: β₂-agonists includingalbuterol, levalbuterol, pirbuterol, artformoterol, formoterol,salmeterol, salbutamol, terbutaline, bitolterol, fluticasone, budesonideand anticholinergics including ipratropium, ipratropium bromide,oxitropium and tiotropium; corticosteroids, glucocorticoids includingoral, systemic and inhaled glucocorticoids and including beclomethasone,budesonide, flunisolide, fluticasone, mometasone, triamcinolone,methyprednisolone, prednisolone, prednisone, ciclesonide; leukotrienemodifiers including montelukast, zafirlukast, pranlukast and zileuton;mast cell stabilizers including cromolyn and nedocromil; epinephrine,ephedrine, methylxanthines including theophylline, aminophylline,combination drugs including ipratropium and albuterol, fluticasone andsalmeterol, budesonide and formoterol; antihistamines includinghydroxyzine, rupatadine, diphenhydramine, ketotifen, norketotifen,loratadine, cetirizine, and hydrocortisone; immune system modulatingdrugs including tacrolimus and pimecrolimus; cyclosporine; azathioprine;mycophenolatemofetil; IgE blockers including omalizumab, andcombinations thereof.

In some embodiments, a method for treating an allergic disease in asubject having a known allergen sensitivity can include theadministration of a compound of Formula I in combination with aninjection of increasing doses of the known allergen to induce toleranceto the allergen and to prevent further allergic reactions. Allergeninjection therapy (allergen immunotherapy) is known to reduce theseverity of allergic rhinitis. While it is possible for allergeninjection therapy to be associated with the risk of side effects such asanaphylactic shock, the use of a composition of the invention andoptionally an additional therapeutic agent known in the treatment of theallergy in question, in combination with an allergen can avoid many ofthe side effects.

In some cases the subject is exposed to an allergen, an allergeninducing solution, or an allergen extract in addition to being treatedwith a composition of the invention either in the absence or presence ofthe optional additional therapeutic agent. In this particular method,the subject is said to be exposed to the allergen, allergen inducingsolution, or allergen extract. As used herein, the term “exposed to”refers to either the active step of contacting the subject with anallergen or the passive exposure of the subject to the allergen,allergen inducing solution, or allergen extract in vivo. Methods of theactive exposure of a subject to an allergen are well-known in the art.In general, an allergen, an allergen inducing solution, or an allergenextract is administered directly to the subject by any means such asintravenous, intramuscular, oral, transdermal, mucosal, intranasal,intratracheal, or subcutaneous administration. The allergen, allergeninducing solution, or allergen extract can be administered systemicallyor locally. A subject is passively exposed to an allergen, an allergeninducing solution, or an allergen extract if the allergen, allergeninducing solution, or allergen extract becomes available for exposure tothe immune cells in the body. A subject may be passively exposed to anallergen, an allergen inducing solution, or an allergen extract, forinstance, by entry of an allergen into the body when the allergen ispresent in the environment surrounding the subject, i.e. pollen.

As used herein, the term “prevent”, “prevented”, or “preventing” whenused with respect to the treatment of an allergic or asthmatic disorderrefers to a prophylactic treatment which increases the resistance of asubject to an allergen, in other words, decreases the likelihood thatthe subject will develop an allergic or asthmatic response to theallergen as well as a treatment after the allergic or asthmatic disorderhas begun in order to fight the allergy/asthma, e.g., reduce oreliminate it altogether or prevent it from becoming worse.

In another aspect, the invention includes a method of decreasing thedose of an additional therapeutic agent by administering to a subjecthaving asthma or allergy or at risk of developing asthma or allergy anadditional therapeutic agent in a sub-therapeutic dosage in combinationwith a compound of the invention, wherein the combination of thesub-therapeutic dose of the additional therapeutic agent and thecompound of the invention produce a therapeutic result in the preventionor treatment of asthma or allergy in the subject. The method allows alower dose of the additional therapeutic agent to be used. This providesseveral advantages, including lower costs associated with using lessdrugs and less chances of inducing side effects resulting from themedications by using lower doses.

According to other aspects, the invention provides methods of treatingor preventing asthma and/or allergy by administering a compound of theinvention and an additional therapeutic agent in different dosingschedules. In one aspect, the invention is a method of preventing ortreating asthma or allergy by administering to a subject a compound ofthe invention in an effective amount for modulating the immune responseand subsequently administering to the subject an additional therapeuticagent. In other aspects, the invention is a method of preventing ortreating asthma or allergy by administering to a subject an additionaltherapeutic agent in an effective amount for providing some symptomaticrelief and subsequently administering a compound of the invention to thesubject.

Kits

The present invention also provides a kit comprising a composition ofthe invention and a delivery device. The compositions may convenientlybe presented in single or multiple unit dosage forms as well as in bulk,and may be prepared by any of the methods which are well known in theart of pharmacy. The composition, found in the kit, is alreadyformulated together, or in the kit the compounds are separately providedalong with other ingredients, and instructions for its formulation andadministration regime. The kit may also contain other agents, such asthose described elsewhere herein and, for example, when for parenteraladministration, they may be provided with a carrier in a separatecontainer, where the carrier may be sterile. The present composition mayalso be provided in lyophilized form, and in a separate container, whichmay be sterile, for addition of a liquid carrier prior toadministration.

In a specific embodiment, the kit of the present invention comprises acompound of the invention, an applicator, and an instructional materialfor the use thereof. In another embodiment, the kit can comprise acompound of formula I, such as those described elsewhere herein, acontainer holding the compound, and an instructional material. Theskilled artisan can provide the applicator.

Preferably, the kit of the present invention comprises a compound offormula I, a compound of Formula Ia, or a compound of Table 1, orcombinations thereof. More preferably, the kit comprises Compound A.Additionally, the kit can comprise an instructional material and anapplicator for the administration of the compound(s) of the presentinvention for the treatment of allergy or an allergic or respiratorydisease or condition. The kits of the present invention can be used totreat the diseases and conditions disclosed herein. The kits describedin the present invention are not limited to the uses above however, andcan be used in any method derived from the teachings disclosed herein.

The invention is now described with reference to the following Examples.These Examples are provided for the purpose of illustration only and theinvention should in no way be construed as being limited to theseExamples, but rather should be construed to encompass any and allvariations which become evident as a result of the teaching providedherein.

EXAMPLES Example 1 Synthesis of4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one

Scheme I gives4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one(5) by alkylation of norketotifen (2) with3-Bromomethyl-5-methyl-pyridine (4). Compound (4) was obtained bytreatment of 3,5-lutidine (3) with NBS and AIBN in a solvent mixture ofchloroform and carbon tetrachloride. Norketotifen (2) was obtained bytreatment of ketotifen with 1-chloroethyl chloroformate and methanolrespectively. Norketotifen (2) can also be obtained by treatment ofketotifen with vinyl chloroformate. Similarly, Norketotifen (2) can beobtained by treatment of ketotifen with 2,2,2-trichloroethylchloroformate (see U.S. Pat. No. 7,557,128). Alternatively, Norketotifen(2) can be obtained by treatment of ketotifen with cyanogen bromide (vonBraun dealkylation) or ethyl chloroformate (see Helvetica Chimica Acta1976, 59(3), 876), followed by subsequent hydrolysis in basic or acidicaqueous solutions.

Example 2 Synthesis of4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one.(Synthesis Scheme II)

In Scheme II,4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one(5) can be obtained by acylation of norketotifen (2) with5-methyl-nicotinic acid (6) using DCC and HOBt in DMF to give compound(7), which can be reduced with phosphorus oxychloride and sodiumborohydride (see Journal of Medicinal Chemistry 1994, 37, 2697-2703).

Example 3 Synthesis of4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one.(Synthesis Scheme III)

In Scheme III, reaction of compound (8) with the Grignard derivative (9)prepared from 3-(4-chloro-piperidin-1-ylmethyl)-5-methyl-pyridine (SeeReference: Drugs of the Future 1996, 21(10):1032-1036 and Spanish PatentES 2120899) affords alcohol (10), which is finally eliminated HBr anddehydrated by H₂SO₄ to give4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one(5). Alternatively, dehydration of alcohol (10) by HBr gives compound(II), which is treated with piperidine and potassium t-butoxide toafford compound (12). Treatment of compound (12) with aqueoushydrochloride gives4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one(5). Compound (8) can be prepared according to Helvetica Chimica Acta(1976), 59(3):876-877.

Example 4 Synthesis of4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one.(Synthesis Scheme IV)

In Scheme IV,4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one(5) could be synthesized by reaction of compound (13) with the Grignardderivative (9) to give alcohol (14), which is treated with aqueoushydrochloride to afford4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one(5). Compound (13) can be prepared according to Helvetica Chimica Acta(1976), 59(3):876-877.

Example 5 Prophylactic effects of4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneon allergy in vivo: IgE-mediated late phase cutaneous reactions (Ear andfoot swelling)

Mice were given4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one(1 mg/kg) or ketotifen (1 mg/kg) orally twice as per the schedule dosingregimen provided in FIG. 1A as indicated by the numbered dose in acircle. The first dose (indicated by a circled number 1) was given onday 1 before IgE injection and a 2nd dose (indicated by a circled number2) was given on day 2 before dinitrofluorobenzene (DNFB, as an allergen)challenge. Mice were passively sensitized by i.v. injection of 2 μganti-DNP IgE mAb (Sigma). After 24 h, a cutaneous reaction was elicitedby the application of 20 μl of DNFB (0.3% wt/vol, Sigma) inacetone-olive oil (4:1) to both sides of the left hind paw or left ear,and 20 μl of acetone-olive oil to the right hind paw or right ear as acontrol. The thickness of foot pad or ear was measured using a digitalmicrometer after 24 h. The thickness of the right ear or right hind paw(treated with acetone-olive oil only) was used as baseline values. TheDNFB-induced increment of tissue thickness was expressed as thepercentage of the baseline values.

In this animal model, ear and foot swelling are largely induced bycytokines and chemokines released from mast cells. Administration of4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-onestrongly reduced allergen DNFB-induced ear and foot swelling as shown inFIG. 1B. This finding suggests that4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneinhibits mast cell-mediated late-phase allergic inflammation likelythrough inhibiting mast cell cytokine and chemokine production.

Example 6 Prophylactic effects of4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneon allergy in vivo: IgE-mediated passive cutaneous anaphylaxis (Evan'sblue dye leakage)

Mice were given4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one(1 mg/kg) or ketotifen (1 mg/kg) orally as per dosing schedule shown inFIG. 2A. Subsequently, mice were sensitized by intradermal injection of20 ng antidinitrophenyl (DNP) IgE mAb (Sigma) into left ears, whileright ear received saline as a control. After 24 h, mice were challengedby i.v. injection of 100 μg of DNP-Bovine Serum Albumin (BSA) (as anallergen) in 200 μl Evan's blue dye (1% wt/vol, Sigma). Thirty minlater, ear punch (8 mm) was collected in 300 μl of formamide andincubated at 80° C. for 2 h in water bath to extract Evan's blue dye.The absorbance was determined at 620 nm.

In this mice model, the Evan's blue dye leakage is largely induced bymast cell granule associated mediators such as histamine.Granule-associated mediators such as histamine stimulate endothelium andblood vessel smooth muscle cells leading to increased vascularpermeability. Administration of4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-onestrongly reduced allergen (DNP)-induced Evan's blue dye leakage whencompared to the vehicle control shown in FIG. 2B. It is important tonote that the inhibitory effects on both Evan's blue dye leakage andtissue swelling were observed 24 hours after oral administration of4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one,suggesting long-lasting effects of this chemical compound.

Example 7 Therapeutic effects of4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneon allergy in vivo: IgE-mediated late phase cutaneous reactions (Ear andfoot swelling)

To demonstrate the therapeutic effects in vivo of4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one,mice were passively sensitized by i.v. injection of 2 μg anti-DNP IgEmAb. After 24 h, a cutaneous reaction was elicited by the application of20 μL of DNFB (0.3% wt/vol, Sigma) in acetone-olive oil (4:1) to bothsides of the left hind paw or left ear, and 20 μl of acetone-olive oilto the right hind paw or right ear as a control as shown in FIG. 3A.Three hours after DNFB application, mice were given4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one(1 mg/kg, p.o.), ketotifen (1 mg/kg, p.o.) or saline as control asindicated in FIG. 3A by the circled number “1”. The thickness of footpad or ear was measured using a digital micrometer after 24 h of DNFBapplication. The weight of hind paw or ear punch (5 mm) was alsodetermined. The thickness and weight of the right ear or right hind paw(treated with acetone-olive oil only) were used as baseline values. TheDNFB-induced increment of tissue thickness was expressed as thepercentage of the baseline values.

As shown in FIG. 3B, application of4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneafter antigen DNP challenge was found to significantly block DNP-inducedswelling and increase the weight of the ear and the feet in this animalmodel, comparable to ketotifen and in some assays even surpassing theactivity of ketotifen (See foot weight of Compound treated mice in FIG.3B). These results suggest that4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-onehas therapeutic effects on allergic inflammation after allergenchallenge in vivo.

Example 84-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneinhibits allergen-induced cytokine IL-6 production by mast cells invitro

Mouse bone marrow derived mast cells (BMMCs) were resuspended in freshcomplete medium supplemented with TIB141-conditioned medium enriched inIgE directed against trinitrophenyl (TNP) at a ratio of 3:1. BMMCs weretypically sensitized at 0.5 million/ml. Following sensitization, BMMCswere washed extensively with RPMI 1640 supplemented with 10% FBS alone.BMMCs were then treated with4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneor ketotifen at the concentration of 01, 1, 10 or 100 μM for 1 hour andsubsequently stimulated with antigen TNP-BSA (10 ng/ml) for 6 h.Cytokine levels in the cell free supernatant were determined by ELISA.As shown in FIG. 4, treatment of mast cells with4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-onewas found to significantly reduce cytokine IL-6 production by mast cellsand was even more effective than ketotifen at some of the equivalentconcentrations used.

The results provided herein demonstrates that (1):4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneblocks allergen-induced late-phase allergic inflammation in vivo; (2):4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneinhibits allergen-induced passive cutaneous anaphylaxis in vivo; and(3):4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneinhibits allergen-induced cytokine IL-6 production by mast cells invitro.

Example 9 Inhibition of eosinophil proliferation in vitro by4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one

Mouse bone marrow derived eosinophils (1×10⁵ cells/well) were seeded in96 well plates in triplicate and were cultured with IL-5 (50 ng/ml).Eosinophils were treated with4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one(Compound A) or ketotifen for 1 hour. Cells were then pulsed with 0.5μCi of ³H-thymidine for 18 hours. Cells were harvested to glass fiberpaper using a suction manifold and washed extensively to eliminateunincorporated thymidine. Fiber paper was dried and added to vials with2.5 ml of scintillation fluid (Ecolite). Thymidine incorporation wasmeasured on a Wallac beta counter.

The incorporation of ³H-thymidine (eosinophil proliferation) wasquantified by liquid scintillation counting (CPM). Treatment with4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneor ketotifen dose-dependently reduced thymidine incorporation. Theseresults suggest that4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-oneand ketotifen inhibit eosinophil proliferation. Importantly,4-[1-(5-methyl-pyridin-3-ylmethyl)piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-onedemonstrated significantly stronger inhibition on eosinophilproliferation than ketotifen did (*, p<0.01, n=3 experiments) as shownin FIG. 5.

The embodiments and the examples described herein are exemplary and notintended to be limiting in describing the full scope of compositions andmethods of the present technology. Equivalent changes, modifications andvariations of some embodiments, materials, compositions and methods canbe made within the scope of the present technology, with substantiallysimilar results.

What is claimed is:
 1. A selective anti-allergy benzocycloheptathiophenederivative compound of Formula I:

or a pharmaceutically acceptable salt, solvate or prodrug thereof,wherein R₂ is pyridine; R₃ is each independently, hydrogen, halo, OH,—CN, —NO₂, —N═O, —NHOQ₁, —OQ₁, —SOQ₁, —SO₂Q₁, —SON(Q₁)₂, —SO₂N(Q₁)₂,—N(Q₁)₂, —C(O)OQ₁, —C(O)Q₁, —C(O)N(Q₁)₂, —C(═NQ₁)NQ₁-, —NQ₁C(═NQ₁)NQ₁-,—C(O)N(Q₁)(OQ₁), —N(Q₁)C(O)-Q₁, —N(Q₁)C(O)N(Q₁)₂, —N(Q₁)C(O)O-Q₁,—N(Q₁)SO₂Q₁, —N(Q₁)SOQ₁, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy,alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀aralkyl, aralkyloxy, C₄₋₁₀ heteroaryl, or heteroaralkyl, wherein eachC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl,aralkyloxy, C₄₋₁₀ heteroaryl, or C₄₋₁₀ heteroaralkyl, optionallysubstituted with 1-3 substituents independently selected from Q₁ or Q₂;each Q₁ is independently hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, alkoxy,alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ arylalkyl, aralkyloxy,C₄₋₁₀ heterocyclic, or C₄₋₁₀ heteroaryl ring, each optionally including1-3 substituents independently selected from Q₂; each Q₂ is halo,haloalkyl, oxo, oxime, azido, amino, amido, cyano, CN, NO₂, CF₃, OCF₃,OH, —COOH or C₁-C₄ alkyl optionally substituted with 1-3 of halo, oxo,oxime, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)₃H, —NH₂, or —COOH.
 2. Theselective anti-allergy benzocycloheptathiophene derivative compoundaccording to claim 1, wherein R₂ is selected from:


3. The selective anti-allergy benzocycloheptathiophene derivativecompound according to claim 1, wherein R₃ is each independently selectedfrom H, C₁₋₈ alkyl, C₁₋₈ alkenyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl,C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, or C₄₋₁₀ heteroaralkyl.
 4. The selective anti-allergybenzocycloheptathiophene derivative compound according to claim 1,wherein R₃ is H or C₁₋₁₂ alkyl.
 5. The selective anti-allergybenzocycloheptathiophene derivative compound according to claim 1,wherein R₃ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,hexyl, 2-ethylpropyl, and cyclohexyl.
 6. The selective anti-allergybenzocycloheptathiophene derivative compound according to claim 1,wherein R₃ is H or methyl.
 7. A selective anti-allergybenzocycloheptathiophene derivative compound of Formula Ia:

or a pharmaceutically acceptable salt, solvate or prodrug thereof,wherein R₃ is each independently, hydrogen, halo, OH, —CN, —NO₂, —N═O,—NHOQ₁, —OQ₁, —SOQ₁, —SO₂Q₁, —SON(Q₁)₂, —SO₂N(Q₁)₂, —N(Q₁)₂, —C(O)OQ₁,—C(O)Q₁, —C(O)N(Q₁)₂, —C(═NQ₁)NQ₁-, —NQ₁C(═NQ₁)NQ₁-, —C(O)N(Q₁)(OQ₁),—N(Q₁)C(O)-Q₁-N(Q₁)C(O)N(Q₁)₂, —N(Q₁)C(O)O-Q₁-N(Q₁)SO₂Q₁, —N(Q₁)SOQ₁,C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀cycloalkyl, C₄₋₁₀ heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl,aralkyloxy, C₄₋₁₀ heteroaryl, or heteroaralkyl, wherein each C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, alkoxy, alkenoxy, C₄₋₁₀ cycloalkyl, C₄₋₁₀heterocycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ aralkyl, aralkyloxy, C₄₋₁₀heteroaryl, or C₄₋₁₀-heteroaralkyl, optionally substituted with 1-3substituents independently selected from Q₁ or Q₂; each Q₁ isindependently hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, alkoxy, alkenoxy,C₄₋₁₀ cycloalkyl, C₄₋₁₀ aryl, C₄₋₁₀ arylalkyl, aralkyloxy, C₄₋₁₀heterocyclic, or C₄₋₁₀ heteroaryl ring, each optionally including 1-3substituents independently selected from Q₂; each Q₂ is halo, haloalkyl,oxo, oxime, azido, amino, amido, cyano, CN, NO₂, CF₃, OCF₃, OH, —COOH orC₁-C₄ alkyl optionally substituted with 1-3 of halo, oxo, oxime, —CN,—NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)₃H, —NH₂, or —COOH.
 8. The selectiveanti-allergy benzocycloheptathiophene derivative compound according toclaim 7, wherein R₃ is H or C₁₋₈ alkyl.
 9. The selective anti-allergybenzocycloheptathiophene derivative compound according to claim 7,wherein R₃ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,hexyl, 2-ethylpropyl, and cyclohexyl.
 10. The selective anti-allergybenzocycloheptathiophene derivative compound according to claim 7,wherein R₃ is H or methyl.
 11. A selective anti-allergybenzocycloheptathiophene derivative compound comprising at least oneselected from: 1

  C₂₄H₂₂N₂OS 4-(1-Pyridin-3-ylmethyl-piperidin-4-ylidene)-4,9-dihydro-1-thia-benzo[f]azulen-10-one 2

  C₂₅H₂₄N₂OS 4-[1-(4-Methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 3

  C₂₅H₂₄N₂OS 4-[1-(6-Methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 4

  C₂₅H₂₄N₂OS 4-[1-(2-Methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 5

  C₂₄H₂₂N₂OS 4-(1-Pyridin-4-ylmethyl-piperidin-4-ylidene)-4,9-dihydro-1-thia-benzo[f]azulen-10-one 6

  C₂₅H₂₄N₂OS 4-[1-(3-Methyl-pyridin-4-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 7

  C₂₅H₂₄N₂OS 4-[1-(2-Methyl-pyridin-4-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 8

  C₂₅H₂₄N₂OS 4-[1-(6-Methyl-pyridin-2-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 9

  C₂₅H₂₄N₂OS 4-[1-(3-Methyl-pyridin-2-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 10

  C₂₅H₂₄N₂OS 4-[1-(4-Methyl-pyridin-2-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 11

  C₂₅H₂₄N₂OS 4-[1-(5-Methyl-pyridin-2-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one 12

  Molecular Formula = C₂₅H₂₄N₂OS4-[1-(5-Methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one.


12. The selective anti-allergy benzocycloheptathiophene derivativecompound according to claim 1, wherein said compound is present as afumarate salt.
 13. A pharmaceutical composition comprising the selectiveanti-allergy benzocycloheptathiophene derivative compound according toclaim 1 and a pharmaceutically acceptable carrier, vehicle or excipient.14. A pharmaceutical composition comprising a therapeutically effectiveamount of the selective anti-allergy benzocycloheptathiophene derivativecompound according to claim 11, and a pharmaceutically acceptablecarrier, vehicle or excipient.
 15. The pharmaceutical compositionaccording to claim 14, wherein said benzocycloheptathiophene derivativecompound is4-[1-(5-methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one,and a pharmaceutically acceptable carrier, vehicle or excipient.
 16. Apharmaceutical unit-dose composition comprising the selectiveanti-allergy benzocycloheptathiophene derivative compound according toclaim 11 in an amount ranging from about 1 to about 10 milligrams, and apharmaceutically acceptable carrier, vehicle or excipient.
 17. Thepharmaceutical unit-dose composition according to claim 16, wherein saidbenzocycloheptathiophene derivative compound is4-[1-(5-methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one.18. An ophthalmic composition for a treatment of an allergic conditionof an eye, the composition comprising the benzocycloheptathiophenederivative compound according to claim 1 and an ophthalmic acceptablecarrier, vehicle or excipient.
 19. An ophthalmic composition for atreatment of an allergic condition of an eye, the composition comprisingthe benzocycloheptathiophene derivative compound according to claim 11,and an ophthalmic acceptable carrier, vehicle or excipient.
 20. Theophthalmic composition according to claim 19, wherein thebenzocycloheptathiophene derivative compound is present in theophthalmic composition in an amount from about 0.01% to about 0.1%(wt/vol.).
 21. The ophthalmic composition according to claim 20, whereinthe benzocycloheptathiophene derivative compound comprises4-[1-(5-methyl-pyridin-3-ylmethyl)-piperidin-4-ylidene]-4,9-dihydro-1-thia-benzo[f]azulen-10-one.